Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents.

Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of small-molecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.

Screening for maternal cytomegalovirus infection during pregnancy and pregnancy outcome in patients with liver disease: an observational study.

BACKGROUND: Cytomegalovirus (CMV) infection among pregnant females could induce CMV hepatitis with possible changes in liver stiffness measurement (LSM) which could be reversibly increased during normal pregnancies, particularly in the third trimester. This study aimed to detect the prevalence of CMV infection among pregnant females with and without chronic liver disease and to evaluate the effects of CMV infection on LSM and pregnancy outcomes in comparison to non-CMV-infected pregnant females. METHODS: This is an observational prospective study that included 201 pregnant ladies presented to the liver disease with pregnancy clinic, Cairo University from March 2018 to April 2019. We assessed the laboratory results, abdominal ultrasonography, LSM using ARFI elastography, and pregnancy outcomes. RESULTS: Two hundred and one pregnant ladies were divided into ; group 1: pregnant ladies with normal pregnancy (n = 128), group 2: pregnant ladies with chronic liver diseases not related to pregnancy (n = 35), and group 3: pregnant ladies with pregnancy-related liver diseases (n = 38). Positive CMV serology (either/or, +ve CMV-IgM, IgG) was detected in 106/201 patients (52.74%), and fifteen of them had an active infection (IgG +, IgM+, PCR+). Pregnant females with chronic liver diseases not related to pregnancy had significantly higher serum levels of CMV IgM, IgG, and PCR. Moreover, LSM had a significant correlation with CMV IgG and CM_PCR in normal pregnant ladies. Maternal mortality occurred only in pregnant females with chronic liver diseases in 5.7% (2/35). CONCLUSION: Maternal CMV infection carries a significant risk to pregnant females with chronic liver disease. Routine CMV screening for women planning to be pregnant, especially those with chronic liver disease could help to avoid bad maternal and fetal outcomes.

Anxiety, depression and coping strategies among chronic medical patients with coronavirus disease-2019: a multicenter follow-up cohort study.

BACKGROUND: Studies have shown that COVID-19 patients experience high levels of anxiety, depression, and stress during the pandemic. Patients adopt different coping strategies to reduce their psychological distress. AIM: To compare the immediate and long-term psychological impact of COVID-19 disease on patients with and without chronic medical illnesses (CMI) and identify coping styles of both groups during the peak of COVID-19 disease in Egypt. METHODS: This is a cohort follow-up study, that included an online survey consisting of General Health Questionnaire-12, Taylor Manifest Anxiety Scale, Beck Depression Inventory and Brief-COPE scale. The Post-Traumatic Stress Disorder (PTSD) Checklist was completed after 6 months. Questionnaires were distributed to adult patients with a confirmed diagnosis of SARS-CoV-2 virus infection during their quarantine in Egypt. RESULTS: There was no significant difference between the two groups regarding anxiety and depression during the acute infection. Patients without CMI relied significantly on the use of informational support to cope with COVID-19 disease. Patients with CMI continued to show significant depressive symptoms after 6 months without significant PTSD symptoms. CONCLUSIONS: COVID-19 has similar immediate psychological impact on patients with and without CMI. However, patients with CMI continue to show depression on long-term follow-up.

Meta-learning algorithm development to predict outcomes in patients with hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND STUDY AIMS: Prediction of prognosis and treatment outcomes for patients with hepatocellular carcinoma (HCC) is complex for most patients. Machine learning predictive analysis can be used to explore the rich information in electronic health records to discover hidden patterns and relationships. We aimed to develop a noninvasive algorithm for predicting outcome treatment options for patients with HCC. PATIENTS AND METHODS: This cross-sectional study included 1298 patients with Hepatitis C virus-related HCC attending an HCC multidisciplinary clinic, Kasr Al-Aini Hospital, Cairo University, between 2009 and 2016. Using machine learning analysis, we constructed Reduced Error Pruning (REP) decision tree algorithms and applied Auto-WEKA to select the best classifier out of 39 algorithms. RESULTS: The REP-tree algorithm predicted HCC management outcomes with a recall (sensitivity) of 0.658 and a precision (specificity) of 0.653 using only routine data. 854 (65.8%) instances were correctly identified, and 444 (34.2%) instances were incorrectly classified. Out of 31 attributes, liver decompensation was selected by REP-tree as the best predictor of HCC outcome (root node). With Auto-WEKA, the random subspace classifier was chosen as the best predictive algorithm with a recall (sensitivity) of 0.750 and a precision (specificity) of 0.75. There were 974 (75%) correctly classified instances and 324 (25%) incorrectly classified instances, which was better than REP-tree. CONCLUSION: Machine learning analysis explores data to discover hidden patterns and trends and enables the development of models to predict HCC treatment outcomes utilizing simple laboratory data. The random subspace classifier predicted the outcome more accurately than REP-tree.

Assessment of circulating levels of microRNA-326, microRNA-424, and microRNA-511 as biomarkers for hepatocellular carcinoma in Egyptians.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer. Differential expression of microRNAs (miRNAs)-326, miRNA-424, and miRNA-511 has been associated with the diagnosis and prognosis of HCC in different populations. However, limited information is available regarding their expression in Egyptian HCC patients. AIM: To assess the role of circulating miRNAs-326, miRNA-424, and miRNA-511 in Egyptian HCC patients. METHODS: This prospective observational study included 70 HCC patients and 25 healthy controls. The circulating levels of these three miRNAs were evaluated by real-time PCR. Receiver operating characteristic curve analysis was used to test the diagnostic accuracy of microRNA expression levels. RESULTS: All miRNAs were differentially expressed in HCC patients; miRNAs326 and miRNA-424 were upregulated, while miRNA-511 was downregulated. Both miRNA-326 and miRNA-424 showed sensitivity and specificity of 97%, 71.4%, and 52%, 60%, respectively, to differentiate HCC from controls. Moreover, miRNA-326 was associated with survival and could differentiate between Child grades (A vs B); miRNA-424 significantly differentiated early vs intermediate stages of HCC; while miRNA-511 was significantly correlated with response to modified Response Evaluation Criteria in Solid Tumors (mRECIST). CONCLUSION: We conclude that miRNA-326, miRNA-424, and miRNA-511 have diagnostic and prognostic roles in Egyptian patients with hepatitis C virus-related HCC and should be considered for better disease management.

Three regimens for re-treatment failure of Sofosbuvir-based therapy for chronic hepatitis-C genotype-4: a cohort study.

Despite the high sustained virologic response (SVR) rates of direct-acting antiviral (DAAs) therapy, a small number of patients does not eradicate the virus, and these patients represent a challenge. This study aims to compare the outcomes of three second-line regimens for DAAs-experienced patients with chronic hepatitis C (CHC). This prospective observational study was conducted at the Damanhur Viral Hepatitis Center from January 2017 to February 2020. We included patients with CHC who did not achieve SVR after the complete course of Sofosbuvir/Daclatasvir±Ribavirin (SOF/DAC±RBV). The primary endpoint was SVR-12 after re-treatment. This study included 360 patients (with a mean age of 51.53±11.38 years). Approximately 51.1% of the patients were males, and 65.5% had liver cirrhosis. All patients of group 1 (45 patients) received SOF/VEL/VOX over 12-weeks; SVR-12 was achieved in 44 patients (97.8%). Group 2 (28 patients) received SOF/DAC/RBV over 24-weeks; (one patient was lost during follow-ups and one patient discontinued treatment due to hepatic decompensation). SVR-12 was achieved in 25 patients (96.2%). Group 3 (287 patients) received SOF/Ombitasvir/Paritaprevir/Ritonavir/RBV) over 12-weeks. Eight patients were lost during follow-ups, and one patient discontinued treatment due to grade 4 adverse events. SVR-12 was achieved in 276 patients (99.3%). There was no difference between the groups regarding their age, gender distribution, baseline viral load or comorbidities. Adverse events (thrombocytopenia, anemia, hyperbilirubinaemia and prolonged INR) were significantly higher in group 3, while group 1 did not experience any. The three studied retreatment regimens can be used for DAAs treatment-experienced patients considering availability. The SOF/VEL/VOX combination had the least adverse events.

Seven gene signature explores the impact of DAAs on the appearance of hepatocellular carcinoma in HCV infected patients.

HCV damages the hepatocytes ending with hepatocellular carcinoma (HCC). The direct-acting antivirals (DAAs) treatment has raised hopes for reducing the incidence of HCC. However, several scientific debate regarding the impact of DAAs on the occurrence of HCC in patients with cirrhosis. We aimed to study the Cirrhosis Risk Score (CRS), several clinical factors and tumor characteristics between patients who developed HCC either with or without DAAs treatment "DAA-exposed HCC patients" and "DAA-unexposed HCC patients". Methods: CRS was assessed via genotyping by allelic discrimination assays in HCV patients who developed de novo HCC (with DAAs (DAA-exposed HCC patients, n = 50), and without DAAs treatment (DAA-unexposed HCC patients, n = 40)). APRI, FIB-4 scores, and tumor characteristics were assessed. Results: Around 60% and 48% of DAA-exposed HCC patients and DAA-unexposed HCC patients; respectively had high CRS scores without significant difference. DAA-exposed HCC patients showed elevated Albumin, Hemoglobin and decreased ALT, AST compared with DAA-unexposed HCC patients (P = 0.002, 0.04, <0.001 and 0.006; respectively). FIB4 and APRI didn't reach the statistical difference between the studied groups. DAA-exposed HCC patients have higher overall survival (OS) than DAA-unexposed HCC patients (median: 30 & 15 months; respectively (p = 0.019)). Moreover, no significant differences were observed between the two groups in their focal lesion characteristics. Conclusion: All studied patients are genetically predisposed to develop HCC. Moreover, DAAs significantly improved the OS and the biochemical parameters. No differences between the two groups were detected regarding their tumor characteristics. Accordingly, the appearance of HCC after treatment is attributed to the natural course of cirrhosis.

RECK gene polymorphisms in hepatitis B-related hepatocellular carcinoma: A case-control study.

BACKGROUND AND STUDY AIMS: Chronic hepatitis B (CHB) infection is a major risk factor for hepatocellular carcinoma (HCC). The RECK gene is a critical tumor suppressor gene. This study aimed to assess the association between RECK gene single nucleotide polymorphisms (SNPs) and the development of HCC in Egyptian patients with chronic hepatitis B. PATIENTS AND METHOD: In this case-control study, we enrolled patients with CHB from the Gastroenterology Department, Benha University, from June 2016 to February 2018. The RECK gene SNP rs10814325 was identified using real-time PCR allelic discrimination via TaqMan SNP genotyping assays (Applied Biosystems, USA). RESULTS: We enrolled 140 participants in this study. The participants were divided into Group I, which comprised 50 participants with CHB only, Group II, which comprised 50 participants with CHB and HCC, and Group III, which comprised 40 healthy participants. A significantly higher hepatitis B virus DNA viremia level was found in patients with HCC. The predominant RECK genotype was the T/T allele, followed by the T/C allele; however, no significant difference in the distribution of RECK gene SNPs was found between the study groups. No statistically significant difference in RECK gene SNPs was reported among patients with HCC of different Child classes or based on the number, site, size of HCC, and lymph node involvement. Receiver operating characteristic curves showed that a serum alpha-fetoprotein level of 92 ng/ml was 96 % sensitive and 100 % specific for the detection of HCC, with an area under the operating characteristic curve of 0.98. CONCLUSION: RECK gene SNPs have no significant association with the development and characteristics of hepatitis B-related HCC in Egyptian patients.

Changes in Serum Interferon Gamma and Interleukin-10 in Relation to Direct-Acting Antiviral Therapy of Chronic Hepatitis C Genotype 4: A Pilot Study.

Introduction: This study analyzes the changing levels of circulating inflammatory cytokines Interferon gamma (IFN-γ) and interleukin (IL)-10 (as the main cytokines of T-helper-1 and T-helper-2 immune responses) in patients with chronic hepatitis C virus (HCV) infection undergoing therapy with direct-acting antivirals (DAAs) and to correlate them with laboratory markers. Methods: This Pilot study included 50 HCV monoinfected patients who received DAAs for 12 or 24 weeks. They were followed up monthly during therapy and 3 months after the end of the treatment. Liver disease was determined by transient elastography, in addition to FIB-4 indices. Analysis of IFN-gamma and IL-10 was carried out using an enzyme-linked immunosorbent assay. Results: All patients carried HCV genotype 4. The Sustained virological response was 100% and 92% in cirrhotics and noncirrhotics, respectively. There was no significant difference between groups in baseline IL-10 or IFN-gamma. In noncirrhotics, IL-10 showed a significant reduction at Week 4 after treatment start. In cirrhotics, IL-10 showed a significant reduction at Week 4 after treatment starts and a significant reduction at Week 12 after the end of the treatment. At Week 12 after the end of the treatment, serum IL-10 levels were significantly lower in cirrhotics. IFN-γ showed nonsignificant changes in noncirrhotics. A significant increase of IFN-γ occurred in cirrhotics from Week 4 after treatment starts to 12 weeks after the end of the treatment. IFN-γ was significantly higher in cirrhotics at Week 12 after the end of the treatment. IFN-γ and IL-10 showed different correlations with laboratory markers. Conclusion: Viral eradication induced by DAAs caused a significant change in IL-10 and IFN-gamma.

Patterns of liver profile disturbance in patients with COVID-19.

Fever and cough are the most common clinical symptoms of coronavirus disease 2019 (COVID-19), but complications (such as pneumonia, respiratory distress syndrome, and multiorgan failure) can occur in people with additional comorbidities. COVID-19 may be a new cause of liver disease, as liver profile disturbance is one of the most common findings among patients. The molecular mechanism underlying this phenomenon, however, is still unknown. In this paper, we review the most current research on the patterns of change in liver profile among patients with COVID-19, the possible explanation for these findings, and the relation to pre-existing liver disease in these patients.

Plasma cell-free DNA integrity index and hepatocellular carcinoma treated or not with direct-acting antivirals: A case-control study.

BACKGROUND AND STUDY AIMS: The clinical value of the cell-free DNA (cf-DNA) integrity index as a diagnostic biomarker of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) was investigated and correlated with alpha-fetoprotein (AFP). PATIENTS AND METHODS: This case-control study was conducted on 160 patients with HCV genotype 4-related liver cirrhosis. Group 1 consisted of 80 patients with HCC, including 40 patients naïve to direct-acting antivirals (DAAs) and 40 patients who received DAAs and achieved sustained virological response. Group 2 comprised 80 patients with cirrhosis without HCC. Plasma cf-DNA integrity index using ALU 115 and ALU 247 sequences was assessed using SYBR Green-based real-time polymerase chain reaction (RT-PCR). The cf-DNA integrity index was calculated as the ratio of Q247/Q115 where Q115 and Q247 are the ALU-qPCR results obtained using ALU 115 and ALU 247, respectively. RESULTS: Patients with HCC had significantly lower plasma cf-DNA integrity index than those with liver cirrhosis. No significant difference in the cf-DNA integrity index was observed between patients with HCC who received DAAs and those who did not. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve of 0.965 and 0.886 for detecting HCC using the cf-DNA integrity index and AFP, respectively. The combination of the cf-DNA integrity index and AFP improved the sensitivity from 81.6% to 94.7%, positive predictive value from 93.4% to 94.7%, negative predictive value from 84.4% to 94.9%, and accuracy from 88.4% to 94.8%. CONCLUSION: The cf-DNA integrity index can predict the occurrence of HCV genotype 4-related HCC. No significant difference in the cf-DNA integrity index was observed between patients with HCC who received DAAs and those without previous DAAs. The combination of the cf-DNA integrity index and AFP provides better HCC prediction accuracy.

Acoustic radiation force impulse to measure liver stiffness and predict hepatic decompensation in pregnancy with cirrhosis: A cohort study.

BACKGROUND AND STUDY AIMS: Pregnancy in association with cirrhosis is a rather uncommon and highly risky situation for both mother and child. We aim to study all factors and the utility of liver stiffness (LS) measurement by Acoustic Radiation Force Impulse elastography (ARFI) to predict hepatic decompensation in pregnant cirrhotic patients. PATIENTS AND METHODS: We prospectively recruited 224 pregnant women at the multidisciplinary clinic of liver disease with pregnancy, Cairo University. LS was measured using ARFI (Siemens ACUSON S3000 ultrasound system) during the second trimester and 8-12 weeks post-delivery. The outcome of pregnancy and the incidence of hepatic decompensation were assessed. RESULTS: Our cohort comprised 128 normal pregnancies, 37 patients with pregnancy-related liver disease (Intrahepatic cholestasis (n = 6), preeclampsia (n = 23), and hyperemesis gravidarum (n = 8)) and 59 patients with an established chronic liver disease not related to pregnancy. In all patients, LS significantly decreased after delivery from 1.19 m/s to 0.94 m/s (P < 0.001). In multivariate analysis, LS was an independent predictor for the outcome of pregnancy in all patients (odds ratio (OR) = 5.442 (3.01-6.82), cut-off = 1.21 m/s). Patients with cirrhosis, mean LS was 1.57 ± 0.66 m/s and 26 (44%) patients had hepatic decompensation (hepatocellular jaundice (n = 8), ascites (n = 9) and variceal bleeding (n = 6)). In multivariate analysis; LS, platelets, albumin, and bilirubin were independent predictors of decompensation post-delivery and the OR for LS was 6.141(4.32-7.98). The optimal cut off value of LS to predict decompensation was 1.46 m/s (8.4 kPa) with AUROC of 0.827. CONCLUSION: LS can be used to predict hepatic decompensation after delivery in pregnant women with manifest cirrhosis.

Prediction of mortality in hospitalized Egyptian patients with Coronavirus disease-2019: A multicenter retrospective study.

We aimed to assess the epidemiological, clinical, and laboratory characteristics associated with mortality among hospitalized Egyptian patients with COVID-19. A multicenter, retrospective study was conducted on all polymerase chain reaction (PCR)-confirmed COVID-19 cases admitted through the period from April to July 2020. A generalized linear model was reconstructed with covariates based on predictor's statistical significance and clinically relevance. The odds ratio (OR) was calculated by using stepwise logistic regression modeling. A total of 3712 hospitalized patients were included; of them, 900 deaths were recorded (24.2%). Compared to survived patients, non-survived patients were more likely to be older than 60 years (65.7%), males (53.6%) diabetic (37.6%), hypertensive (37.2%), and had chronic renal insufficiency (9%). Non-survived patients were less likely to receive azithromycin (p <0.001), anticoagulants (p <0.001), and steroids (p <0.001). We found that age ≥ 60 years old (OR = 2.82, 95% CI 2.05-3.86; p <0.0001), diabetes mellitus (OR = 1.58, 95% CI 1.14-2.19; p = 0.006), hypertension (OR = 1.69, 95% CI 1.22-2.36; p = 0.002), chronic renal insufficiency (OR = 3.15, 95% CI 1.84-5.38; p <0.0001), tachycardia (OR = 1.65, 95% CI 1.22-2.23; p <0.001), hypoxemia (OR = 5.69, 95% CI 4.05-7.98; p <0.0001), GCS <13 (OR 515.2, 95% CI 148.5-1786.9; p <0.0001), the use of therapeutic dose of anticoagulation (OR = 0.4, 95% CI 0.22-0.74, p = 0.003) and azithromycin (OR = 0.16, 95% CI 0.09-0.26; p <0.0001) were independent negative predictors of mortality. In conclusion, age >60 years, comorbidities, tachycardia, hypoxemia, and altered consciousness level are independent predictors of mortality among Egyptian hospitalized patients with COVID-19. On the other hand, the use of anticoagulants and azithromycin is associated with reduced mortality.

P53 is a risk factor of de-novo hepatitis C-related hepatocellular carcinoma treated with direct-acting antivirals: a case-control study.

BACKGROUND: The mechanisms underlying de-novo hepatocellular carcinoma (HCC) after direct-acting antivirals (DAAs) is still under investigation. This work aims to study P53 and hepatocyte growth factor (HGF) as possible diagnostics of de-novo hepatocellular carcinoma (HCC) following DAAs in comparison to alpha-fetoprotein (AFP). METHOD: This case-control study included 166 patients with liver cirrhosis divided into group-1: patients without HCC (n = 50), group-2: patients with de-novo HCC following DAAs, and achieved sustained virological response (n = 50), and group-3: patients with HCC without DAAs (n = 66). P53 antibody and HGF were determined using a quantitative sandwich enzyme immunoassay technique (Cusabio Co, Houston, USA). RESULTS: Patients with HCC showed significantly higher HGF. Patients with de-novo HCC following DAAs had significantly higher P53 than HCC without DAAs (P < 0.0001). The multiple logistic regression analysis showed that the P53 levels were significantly associated with susceptibility to de-novo HCC (P value = 0.004). The best overall formula was constructed for HCC diagnosis by entering significant markers into the regression model. A three markers model was developed = (1.22 + AFP X 0.002 + HGF X 0.001 + P53 X 0.001). The medians (percentiles) of combined three markers were 1.8 (1.0-2.1) in liver cirrhosis and 2.2 (2.0-2.9) in all HCC (P < 0.00001). The AUC of combined markers was greater than a single marker. The AUC was 0.87 to differentiate HCC from liver cirrhosis; AUC 0.91 to differentiate de-novo HCC after DAAs from liver cirrhosis. CONCLUSION: P53 may serve as a diagnostic marker for de-novo HCC after DAAs therapy. HGF may serve as a diagnostic marker for HCC but not specific for de-novo HCC after DAAs therapy.

Survival and recurrence rates of hepatocellular carcinoma after treatment of chronic hepatitis C using direct acting antivirals.

BACKGROUND: Conflicting studies were proposed either suggested or denied the relationship between early hepatocellular carcinoma (HCC) recurrence and the use of direct-acting antivirals (DAAs) for chronic hepatitis C management. AIM OF THE STUDY: To evaluate HCC recurrence rate post-DAAs and potential predictive factors.Study This prospective cohort study included all HCC patients achieved complete response attending our multidisciplinary HCC clinic, Cairo University, from November 2013 to February 2018. Group I (60 patients) who received DAAs after HCC ablation and group II (273 patients) who were DAAs-untreated. We studied factors that could play a role in HCC recurrence. RESULTS: The sustained virological response rate was 88.3% among DAA-treated patients. HCC recurrence rate was 45% in the post-DAA group vs. 19% in the non-DAAs group; P < 0.001. Mean survival was significantly higher in the post-DAA group (34.23 ± 16.16 vs. 23.92 ± 13.99 months respectively; P value <0.001). There was a significant correlation between HCC recurrence rate and age, male gender, mean size of tumors and time interval between complete HCC ablation and occurrence of HCC recurrence. CONCLUSION: Our study reports high rate of HCC recurrence post-DAA therapy in patients treated with transarterial chemoembolization but not in those treated with curative measures. DAA therapy after curative treatment for HCC led to significantly earlier HCC recurrence, which correlated with specific clinic-pathologic features in our prospective single-institution study. However, future independent prospective randomized studies are warranted to evaluate this correlation which may lead to a change in the current standard-of-care approach to patients with hepatitis C virus-related HCC.

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

OBJECTIVE: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Schistosoma mansoni infection and the occurrence, characteristics, and survival of patients with hepatocellular carcinoma: an observational study over a decade.

Schistosoma mansoni infection (SMI) is suspected to be directly and indirectly involved in hepato-carcinogenesis. This study evaluated the association of a previous SMI with hepatocellular carcinoma (HCC) development, patients, tumor characteristics, treatment outcomes, and survival. This observational study included patients with HCC with and without previous SMI who presented to the multidisciplinary HCC clinic, Kasr-Alainy hospital (November 2009 to December 2019). It also included 313 patients with liver cirrhosis without HCC. Clinical and laboratory features of the patients (complete blood count, liver/renal functions , alpha-fetoprotein, and hepatitis B/C status), tumor characteristics (Triphasic CT and/or dynamic MRI), liver stiffness (transient elastography), HCC treatment outcome, and overall survival were studied. This study included 1446 patients with HCC; 688(47.6%) composed group-1, defined by patients having a history of SMI, and 758(52.4%) were in group-2 and without history of SMI. Male sex, smoking, diabetes mellitus, splenomegaly, deteriorated performance status, synthetic liver functions, and platelet count were significantly higher in group-1. The groups did not differ with regard to liver stiffness, tumor characteristics, or the occurrence of post-HCC treatment hepatic decompensation or recurrence. HCC treatment response was better in group-2. Group-1 showed lower sustained virological response to hepatitis C direct-acting antivirals (DAAs) compared with group-2 (60% versus 84.3%, respectively, P = 0.027). Prior SMI was associated with HCC (adjusted odds ratio = 1.589, 95% confidence interval = 1.187-2.127), and it was concluded that it increases the risk of HCC. In addition, it significantly affects the performance status, laboratory characteristics, response to DAAs, and overall survival.

Three regimens for re-treatment failure of Sofosbuvir-based therapy for chronic hepatitis-C genotype-4: a cohort study

ABSTRACT Despite the high sustained virologic response (SVR) rates of direct-acting antiviral (DAAs) therapy, a small number of patients does not eradicate the virus, and these patients represent a challenge. This study aims to compare the outcomes of three second-line regimens for DAAs-experienced patients with chronic hepatitis C (CHC). This prospective observational study was conducted at the Damanhur Viral Hepatitis Center from January 2017 to February 2020. We included patients with CHC who did not achieve SVR after the complete course of Sofosbuvir/Daclatasvir±Ribavirin (SOF/DAC±RBV). The primary endpoint was SVR-12 after re-treatment. This study included 360 patients (with a mean age of 51.53±11.38 years). Approximately 51.1% of the patients were males, and 65.5% had liver cirrhosis. All patients of group 1 (45 patients) received SOF/VEL/VOX over 12-weeks; SVR-12 was achieved in 44 patients (97.8%). Group 2 (28 patients) received SOF/DAC/RBV over 24-weeks; (one patient was lost during follow-ups and one patient discontinued treatment due to hepatic decompensation). SVR-12 was achieved in 25 patients (96.2%). Group 3 (287 patients) received SOF/Ombitasvir/Paritaprevir/Ritonavir/RBV) over 12-weeks. Eight patients were lost during follow-ups, and one patient discontinued treatment due to grade 4 adverse events. SVR-12 was achieved in 276 patients (99.3%). There was no difference between the groups regarding their age, gender distribution, baseline viral load or comorbidities. Adverse events (thrombocytopenia, anemia, hyperbilirubinaemia and prolonged INR) were significantly higher in group 3, while group 1 did not experience any. The three studied retreatment regimens can be used for DAAs treatment-experienced patients considering availability. The SOF/VEL/VOX combination had the least adverse events.

Survival and outcomes for co-infection of chronic hepatitis C with and without cirrhosis and COVID-19: A multicenter retrospective study.

BACKGROUND: Chronic liver disease, particularly cirrhosis, is associated with worse outcomes in patients infected with coronavirus disease 2019 (COVID-19). AIM: To assess outcomes of COVID-19 infection among patients with pre-existing hepatitis C with or without liver cirrhosis. METHODS: This multicenter, retrospective cohort study included all cases of confirmed co-infection of severe acute respiratory syndrome coronavirus 2 and chronic hepatitis C with or without liver cirrhosis who were admitted to six hospitals (Al-Sahel Hospital, Al-Matareya Hospital, Al-Ahrar Hospital, Ahmed Maher Teaching Hospital, Al-Gomhoreya Hospital, and the National Hepatology and Tropical Medicine Research Institute) affiliated with the General Organization for Teaching Hospitals and Institutes in Egypt. Patients were recruited from May 1, 2020, to July 31, 2020. Demographic, laboratory, imaging features, and outcomes were collected. Multivariate regression analysis was performed to detect factors affecting mortality. RESULTS: This retrospective cohort study included 125 patients with chronic hepatitis C and COVID-19 co-infection, of which 64 (51.20%) had liver cirrhosis and 40 (32.00%) died. Fever, cough, dyspnea, and fatigue were the most frequent symptoms in patients with liver cirrhosis. Cough, sore throat, fatigue, myalgia, and diarrhea were significantly more common in patients with liver cirrhosis than in non-cirrhotic patients. There was no difference between patients with and without cirrhosis regarding comorbidities. Fifteen patients (23.40%) with liver cirrhosis presented with hepatic encephalopathy. Patients with liver cirrhosis were more likely than non-cirrhotic patients to have combined ground-glass opacities and consolidations in CT chest scans: 28 (43.75%) vs 4 (6.55%), respectively (P value < 0.001). These patients also were more likely to have severe COVID-19 infection, compared to patients without liver cirrhosis: 29 (45.31%) vs 11 (18.04%), respectively (P value < 0.003). Mortality was higher in patients with liver cirrhosis, compared to those with no cirrhosis: 33 (51.56%) vs 9 (14.75%), respectively (P value < 0.001). All patients in Child-Pugh class A recovered and were discharged. Cirrhotic mortality occurred among decompensated patients only. A multivariate regression analysis revealed the following independent factors affecting mortality: Male gender (OR 7.17, 95%CI: 2.19-23.51; P value = 0.001), diabetes mellitus (OR 4.03, 95%CI: 1.49-10.91; P value = 0.006), and liver cirrhosis (OR 1.103, 95%CI: 1.037-1.282; P value < 0.0001). We found no differences in liver function, COVID-19 disease severity, or outcomes between patients who previously received direct-acting antiviral therapy (and achieved sustained virological response) and patients who did not receive this therapy. CONCLUSION: Patients with liver cirrhosis are susceptible to higher severity and mortality if infected with COVID-19. Male gender, diabetes mellitus, and liver cirrhosis are independent factors associated with increased mortality risk.

Hepatic and gastrointestinal disturbances in Egyptian patients infected with coronavirus disease 2019: A multicentre cohort study.

BACKGROUND: Various liver and gastrointestinal involvements occur in patients with coronavirus disease 2019 (COVID-19) at variable prevalence. Most studies report mild liver function disturbances correlated with COVID-19 severity, though liver failure is unusual. AIM: To study liver and gastrointestinal dysfunctions in Egyptian patients with COVID-19 and their relation to disease outcomes. METHODS: This multicentre cohort study was conducted on 547 Egyptian patients from April 15, 2020 to July 29, 2020. Consecutive polymerase chain reaction-confirmed COVID-19 cases were included from four quarantine hospitals affiliated to the Egyptian ministry of health. Demographic information, laboratory characteristics, treatments, fibrosis-4 (FIB-4) index, COVID-19 severity, and outcomes were recorded and compared according to the degree of liver enzyme elevation and the presence of gastrointestinal symptoms. Follow-ups were conducted until discharge or death. Regression analyses were performed to determine the independent factors affecting mortality. RESULTS: This study included 547 patients, of whom 53 (9.68%) died during hospitalization and 1 was discharged upon his request. Patients' mean age was 45.04 ± 17.61 years, and 21.98% had severe or critical COVID-19. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were available for 430 and 428 patients, respectively. In total, 26% and 32% of patients had elevated ALT and AST, respectively. Significant liver injury with ALT or AST elevation exceeding 3-fold was recorded in 21 (4.91%) and 16 (3.73%) patients, respectively. Male gender, smoking, hypertension, chronic hepatitis C, and lung involvement were associated with elevated AST or ALT. AST was elevated in 50% of patients over 60-years-old. FIB-4 was significantly higher in patients admitted to the intensive care unit (ICU), those with more severe COVID-19, and non-survivors. The independent variables affecting outcome were supplementary vitamin C intake (1 g daily capsules) [odds ratio (OR): 0.05, 95% confidence interval (CI): 0.008-0.337]; lung consolidation (OR: 4.540, 95%CI: 1.155-17.840); ICU admission (OR: 25.032, 95%CI: 7.110-88.128); and FIB-4 score > 3.25 (OR: 10.393, 95%CI: 2.459-43.925). Among 60 (13.98%) patients with gastrointestinal symptoms, 52 (86.67%) had diarrhoea. Patients with gastrointestinal symptoms were predominantly females with higher body mass index, and 50 (83.40%) patients had non-severe COVID-19. CONCLUSION: Few Egyptian patients with COVID-19 developed a significant liver injury. The independent variables affecting mortality were supplementary vitamin C intake, lung consolidation, ICU admission, and FIB-4 score.