Multidisciplinary consensus recommendations for management of hepatocellular carcinoma in Middle East and North Africa region.

Hepatocellular carcinoma (HCC) is a growing health concern projected to cross over a million cases worldwide by 2025. HCC presents a significant burden of disease in Middle East and North African (MENA) countries due to a high prevalence of risk factors such as hepatitis C and B infections and rising incidence of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In August 2022, an advisory meeting consisting of experts from 5 MENA countries was convened in an attempt to provide consensus recommendations on HCC screening, early diagnosis, current treatment modalities and unmet medical needs in the region. Data were collected from a pre-meeting survey questionnaire and responses analysed and presented during the advisory meeting. This review summarizes the evidence discussed at the meeting and provides expert recommendations on the management of HCC. The 2022 update of Barcelona clinic liver cancer (BCLC) staging and treatment strategy and its implementation in the MENA region was extensively discussed. A key consensus of the expert panel was that multidisciplinary care is crucial to effective patient management that results in better clinical outcomes and overall survival of the patient. The panel recommended the use of predictive and early response biomarkers to guide clinicians in arriving at more effective therapeutic decisions. The experts also emphasized the role of robust screening/surveillance systems, population-based registries, effective referral pathways and standardization of guidelines to ensure the successful management of HCC in the region.

Impacts of the Egyptian national screening and treatment programme for viral hepatitis C: A cost-effectiveness model.

BACKGROUND & AIMS: Egypt used to have one of the highest prevalences of HCV infection worldwide. The Egyptian Ministry of Health launched a national campaign for the detection and management of HCV to reduce its burden. This study aims to carry out a cost-effectiveness analysis to evaluate the costs and benefits of the Egyptian national screening and treatment programme. METHODS: A disease burden and economic impact model was populated with the Egyptian national screening and treatment programme data to assess direct medical costs, health effects measured in disability-adjusted life years and the incremental cost-effectiveness ratio. The scenario was compared to a historical base case, which assumed that no programme had been conducted. RESULTS: Total number of viremic cases is expected to decrease in 2030 by 86% under the national screening and treatment programme, versus by 41% under the historical base case. Annual discounted direct medical costs are expected to decrease from $178 million in 2018 to $81 million by 2030 under the historical base case, while annual direct medical costs are estimated to have peaked in 2019 at $312 million before declining to $55 million by 2030 under the national screening and treatment programme. Under the programme, annual disability-adjusted life years are expected to decline to 127 647 by 2030, leading to 883 333 cumulative disability-adjusted life years averted over 2018-2030. CONCLUSIONS: The national screening and treatment programme is highly cost-effective by the year 2021, cost-saving by 2029 and expected to save about $35 million in direct costs and $4705 million in indirect costs by 2030.

ADAM10 Gene Polymorphism and Its Relationship to Hepatocellular Carcinoma in Egyptian HCV Patients Receiving Direct-Acting Antiviral Therapies (DAAs).

OBJECTIVE: The aim of this study was to investigate the ADAM 10 rs.653765 SNP genetic polymorphism in the hepatocellular carcinoma occurrence (de novo and post DAAs). METHODS: This study was conducted on 360 participants divided to 4 groups. Group 1: 90 chronic adult patients infected with HCV received DAAs regimens and evolved HCC during the period of follow up. Group 2: Another 90 HCV patients received the same DAAs regimens and did not show HCC manifestations during the same follow up period. Group 3 included 90 de novo HCC patients (did not receive any DAAs). Finally, 90 apparently healthy participants as group 4. Clinical and laboratory data were evaluated, and ADAM 10 genotyping were performed using qPCR. RESULTS: The study showed statistically significant between HCC de novo and HCC deterioration on top of DAAs according to three scoring systems (Child Pugh, BCLC and HKLC) with p- value <0.05. Regarding ADAM10 gene polymorphism, the study showed a significant difference between CC versus CT+TT genotypes of HCC groups according to Child Bugh, BCLC and HKLC staging systems. Yet, no significant difference was found when ADAM10 genotypes and allele frequencies were compared between the four different studied groups. No difference in the survival rate between HCC de novo and on the top of DAAs but more aggressive stages with HCC on top of DAAs. CONCLUSION: ADAM10 genotypes did not show any significant association with HCC. Also, no differences in the death rate recorded between the de novo HCC and HCC post DAAs treatment with statistical significant worse staging of HCC post DAAs and were noted. the study showed a significant difference between CC versus CT+TT genotypes of HCC groups according to Child Bugh, BCLC and HKLC staging systems.
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Evaluation of factors affecting patients' refusal of HCV treatment in a cohort of Egyptian patients.

BACKGROUND: Treatment refusal, defined as active refusal of a patient to receive treatment despite physician recommendations, has not been extensively evaluated before in hepatitis C virus in the era of direct acting antivirals. OBJECTIVE: To investigate the reasons for refusal to receive hepatitis C virus treatment in Egypt. METHODS: an observational study conducted between July 2018 and November 2019 in Egypt. Enrollment was done to all patients who refused to get hepatitis C virus treatment during the national screening and treatment campaign. Reasons for their refusal were identified using a questionnaire as an instrument for data collection. RESULTS: Out of the 220 280 Egyptian hepatitis C virus patients who did not show up to start treatment and were contacted to get therapy, only 84 patients (0.038%) refused to receive treatment. The main reason for their refusal was having concerns about treatment (82.14%) and their main concern was the fear of adverse events (85.5%). Other causes of refusal were non-satisfactory experience at treatment centers (13.09%) and patients preferred to receive complementary and alternative medicines (4.7%). Most patients (65.4%) trusted the efficacy of directly acting antivirals for hepatitis C. None of the study participants was found to suffer from any psychiatric morbidity and the average score of the GHQ-12 was 10.7155. CONCLUSION: Proper health education and awareness regarding hepatitis C virus treatment safety and efficacy is needed to increase treatment acceptance rates.

Seroprevalence of HBV/HCV coinfection among patients with HCV screened during the national campaign for HCV eradication in Egypt.

BACKGROUND AND STUDY AIMS: Little is known about the true prevalence of hepatitis B virus (HBV) coinfection in patients with hepatitis C virus (HCV). This multicenter nationwide study aimed to assess the seroprevalence of HBV among Egyptian patients with HCV and its possible risk factors. PATIENTS AND METHODS: This is a cross-sectional, multicenter, nationwide study. Data were extracted from the National Network of Viral Hepatitis Treatment Centers database. Baseline data of patients proved to be viremic during the national campaign for HCV eradication (October 2018-April 2019) were retrieved. Data included demographics, laboratory tests (HBsAg, CBC, liver biochemical profile, creatinine, AFP, HbA1c, and viral load), FIB-4 score calculation, and abdominal ultrasound results. RESULTS: Results of 297,965 patients showed that HBsAg was positive in 2,347 (0.8%) patients. Patients with HBV/HCV were 57% females and had a mean age of 51 ± 13 years. Patients with positive HBsAg showed significantly more tobacco consumption, intravenous drug abuse, hypertension, and diabetes. No significant difference was noted in HCV viremia between patients with HCV and those with HBV/HCV. Only 14% of patients with HBV/HCV had cirrhosis compared with the 9% of those with HCV; two of them had HCC. CONCLUSION: Although Egypt has a heavy HCV burden, the overall prevalence of HBV is low among patients with HCV infection. Comorbid conditions seem to favor coinfection.

Impact of prothrombin and factor V Leiden mutations on the progression of fibrosis in patients with chronic hepatitis C.

BACKGROUND: The role of thrombotic factors in the pathogenesis and progression of liver fibrosis remains obscure. We aimed to study the relationship between prothrombin G20210A (PT20210) and factor V Leiden (FVL) mutations and the progression of fibrosis and liver function in chronic HCV patients. METHODS: The study included 100 subjects, 88 patients with HCV-related cirrhosis (compensated: 38, decompensated: 50), and 12 controls. Patients with other viral hepatitis or coinfection, inherited metabolic disease, autoimmune hepatitis, hepatic or extrahepatic malignancy, in addition to patients with causes of hypoalbuminemia, elevated bilirubin or prolonged INR not related to cirrhosis were excluded from the study. Relevant clinical data were collected and basic laboratory tests were performed. Liver fibrosis was assessed using APRI and FIB-4 scores. FVL and PT20210 mutations were analyzed. RESULTS: FVL and PT20210 mutations were significantly higher in decompensated vs. compensated patients (32% vs. 5.3%, P = 0.001; 20% vs. 5.3%, 0.043, respectively) and absent in controls. Both mutations significantly correlated to the duration of infection, platelet count and fibrosis scores. PT20210 mutation significantly correlated to serum albumin and INR. Both mutations significantly predicted fibrosis scores, especially PT20210 (AUROC: 0.833 for APRI and 0.895 for FIB-4). CONCLUSIONS: Both mutations are significantly correlated to fibrosis progression and liver profile and could be considered as markers predicting the need for early and different intervention.

Prevalence and clinical characteristics of patients with metabolic dysfunction-associated fatty liver disease with hepatitis C virus infection-a population-based study.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) was proposed in 2020 to identify fatty liver disease associated with metabolic risks. Metabolic abnormalities with hepatitis C virus (HCV) and MAFLD frequently co-exist. However, data on the co-existence are still lacking. AIM: To explore the prevalence and characteristics of metabolic profiles among a large cohort of patients with HCV infection between 2007 and 2020 based on new diagnostic criteria METHODS: We recruited 288,222 patients with chronic HCV infection with demographic data, laboratory parameters, and ultrasound from a web-based registry of the National Committee for Control of Viral Hepatitis in Egypt from 2007 to 2020. RESULTS: Among the participants, 41.9% (95% CI: 41.69-42.05) met diagnostic criteria for MAFLD, with a significant increase in the period 2014-2020 compared to 2007-2013 (43.3% vs. 19%, respectively). Participants with MAFLD had a high prevalence of obesity, diabetes mellitus and hypertension. The prevalences increased significantly over time (obesity: 66.7% vs. 76.9%, p < 0.01; diabetes mellitus: 14.6% vs. 31.5%, p < 0.01; hypertension: 0.9% vs. 7.6%, p < 0.01; prediabetes: 28.8% vs. 25.9%, p < 0.01) for the periods 2007-2013 and 2014-2020, respectively. The percentage of advanced fibrosis by fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) was significantly higher in participants with MAFLD during 2014-2020 than during 2007-2013 (FIB-4; 18.4% vs. 8% and NFS; 17.1% vs. 7%). CONCLUSION: MAFLD is highly prevalent in patients with HCV infection and has risen over time. This rising prevalence parallels the alarming rise in obesity, diabetes mellitus and hypertension. Early detection of metabolic dysfunction in patients with HCV infection is recommended to prevent MAFLD progression.

Nationwide hepatitis C virus screening and treatment of adolescents in Egyptian schools.

Until 2018, Egypt had the highest prevalence of hepatitis C virus (HCV) infection globally, affecting approximately 7% of the population. Despite efforts in diagnosis and treatment since 2006, nearly 2 million individuals with chronic HCV infection had yet to be diagnosed as of early 2018. In December, 2018, a mass HCV screening campaign for adolescents aged 15-18 years was initiated. Among 3 024 325 adolescents screened, the HCV antibody seroprevalence was 11 477 (0·38%), of whom 8187 (78·7%) were HCV RNA-positive. Sustained virological response 12 weeks after completion of treatment (SVR12) was attained by 7327 (99·6%) adolescents with a fixed-dose combination of generic ledipasvir 90 mg plus sofosbuvir 400 mg. Although mass screening in this age group might not be regularly adopted by many health systems and its cost-effectiveness might be lower than the screening of adults and high-risk groups (eg, patients on haemodialysis, people who inject drugs), breaking the chain of transmission in younger populations should lead to a reduction in HCV incidence and complications, and hasten the elimination of the disease.

Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID-19: A randomized controlled trial.

Only a few treatments are approved for coronavirus disease-2019 (COVID-19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID-19 infection. Multicentre parallel randomized controlled open-label trial. One hundred and twenty eligible patients with moderate and severe COVID-19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF-DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF-DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF-DCV with a lower incidence of mortality. On the other hand, adding SOF-RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF-DCV as an add-on to SOC for the treatment of moderate to severe COVID-19 infections.

Pregnancy outcome of anti-HCV direct-acting antivirals: Real-life data from an Egyptian cohort.

We aimed to assess the pregnancy outcome in women with chronic HCV who had negative pregnancy test prior to the anti-HCV course and had unintended pregnancy while on HCV treatment. Hundred patients with a mean age of 30 ± 6.7 y were included and advised to withhold antivirals and continue follow-up in viral hepatitis and obstetrics centres till delivery. All patients received a 12-weeks regimen of anti-HCV [sofosbuvir plus daclatasvir (SOF/DCV): n = 95, SOF/DCV plus ribavirin: n = 3, and paritaprevir/ritonavir/ombitasvir plus ribavirin: n = 2]. Only nine patients completed the full antiviral course against medical advice, and 91 stopped between on-treatment weeks 4 and 8. Eighty-eight patients delivered full-term babies, eight had preterm babies and two had abortions. Of the nine patients who completed the full course of DAAs, seven (77.8%) delivered normal babies, attended their post-treatment week 12 visit, and all (100%) achieved sustained virological response. No major antiviral-related adverse events were reported.

Serum ammonia as a non-invasive marker for early prediction of esophageal varices.

INTRODUCTION: There is a growing need for identification of non-endoscopic, non-invasive methods that can accurately predict esophageal varices (EV). Previous studies found an inconclusive correlation between blood ammonia level and the presence and size of EV. AIM: We aimed at assessing the value of serum ammonia as a non-invasive method for early prediction of EV. PATIENT AND METHODS: The study included 204 patients with HCV-related cirrhosis. The selected patients were categorized into two groups: patients with EV and those without, also patients with no or small EV and with large EV group. All patients underwent a complete biochemical workup, ultrasound and upper GI endoscopy. Child-Pugh class, Model of End-Stage Liver Disease (MELD) score and platelet count/splenic diameter ratio, and serum ammonia level. RESULTS: There was a statistical difference between the two groups of patients regarding the following parameters: serum ammonia, international normalized ratio, portal vein diameter, spleen diameter, Child-Pugh class, MELD score, platelet count/splenic diameter ratio, aspartate aminotransferase-to-platelet ratio index, alanine aminotransferase-to-aspartate aminotransferase ratio, Forns index, FIB-4 and King's score. Serum ammonia could predict the presence of EV using a cutoff value of 82 (µmol/L) with a sensitivity of 92.3%, specificity 92%. In addition, a cutoff of 95.5 (µmol/L) could predict large EV with a sensitivity of 92.7% and a specificity of 92.3%. Serum Ammonia in cirrhosis with large EV was 143 ± 39 µmol/L and in cirrhosis with small/without EV was 80.7 ± 9.7 µmol/L (P < 0.0001). Platelet/spleen ratio was 555.9 ± 187.3 in cirrhosis with EV and 694.4 ± 74.2 in cirrhosis without EV (P < 0.0001). Platelet/spleen ratio was 407.7 ± 107.1 in cirrhosis with large EV and 690.4 ± 103.7 in cirrhosis with small/without EV (P < 0.0001). CONCLUSION: Serum ammonia can accurately predict the presence and the size of EV in patients with liver cirrhosis with high sensitivity and specificity.

Direct acting antivirals are associated with more liver stiffness regression than pegylated interferon therapy in chronic hepatitis C patients.

OBJECTIVES: Extent of post-treatment fibrosis change in patients with different stages of fibrosis not fully known. We aimed to study changes in liver fibrosis in chronic hepatitis C patients who were treated with pegylated interferon/ribavirin (PEG/RBV) or direct acting antivirals (DAAs). METHODS: Retrospective evaluation of results of transient elastography (TE) was done before and 1 year after end of treatment for patients treated with PEG/RBV (n = 268) and DAAs (n = 245). RESULTS: The average age was 45.54 ± 10.64 years; mainly males. All patients in the DAAs group achieved sustained virological response (SVR), unlike 56.3% of the patients in the PEG/RBV group. F3-F4 fibrosis was predominant in the PEG/RBV nonresponder patients (51.3%) and DAAs responders (57.1%). TE decreased 1 year after end of treatment (p = 0.001) in the viral responders of the PEG/RBV group (7.44 ± 4.02 vs. 10.24 ± 7.29 kPa) and DAAs group (12.12 ± 9.21 vs. 16.81 ± 12.84 kPa) respectively. The delta TE change in the DAAs responders was higher than the PEG/RBV responders (p = 0.001) and PEG/RBV nonresponders (p = 0.001). The percentage of patients with liver fibrosis regression was higher in DAAs responders (52.5%) than in PEG/RBV responders (23.3%). CONCLUSION: Treatment with DAAs is associated with fibrosis improvement more than treatment with PEG/RBV in chronic hepatitis C patients.

Elastography and serum markers of fibrosis versus liver biopsy in 1270 Egyptian patients with hepatitis C.

BACKGROUND: Chronic hepatitis C (CHC) is a leading cause of liver fibrosis. OBJECTIVE: To compare utility of liver transient elastography, AST-to-platelet ratio index (APRI), fibrosis-4 index (FIB4), Forns Index and Goteborg University cirrhosis index (GUCI) in predicting fibrosis stage assessed by liver biopsy in Egyptian CHC patients. METHODS: One thousand two-hundred and seventy CHC patients undergoing liver biopsy in preparation for therapy and 40 healthy potential living liver donors had transient elastography and calculation of APRI, FIB4, Forns and GUCI scores on the same day or day preceding the biopsy. RESULTS: Mean age was 39.89 (17-60 years) and most were males (70.7%). All donors had F0 fibrosis, most patients had F1-F2 fibrosis (n = 1011, 79.6%) and 259 (20.4%) had F3-F4 fibrosis. Patients with F3-F4 fibrosis had higher median values of APRI (0.99 vs. 0.46), FIB4 (2.15 vs. 0.95) and Forns (7.34 vs. 4.79) indices, GUCI score (1.16 vs. 0.49) and transient elastography (19.2 vs. 6.2 kPa) (all P = 0.001). For F1 discrimination, AUROC of transient elastography was higher than both Forns and GUCI scores (P = 0.001). APRI, FIB4 and GUCI had lower AUROC than transient elastography for predicting fibrosis stage in F2 and F3 patients (P = 0.001). Transient elastography had the best area under receiver operating characteristic curve for predicting fibrosis stage in F4 patients (P = 0.001). The transient elastography cutoff values (kPa) were F1 (>4.8), F2 (>8.3), F3 (>10.1) and F4 (>13.4). Age, APRI, FIB4, Forns, GUCI and transient elastography were independent predictors of F3-F4 fibrosis. CONCLUSION: Liver elastography is superior to APRI, FIB4, Forns and GUCI scores in predicting fibrosis in CHC patients.

Influence of esophageal variceal bleeding on iron status in chronic hepatitis C patients.

BACKGROUND: Disorders of serum iron balance are frequently observed in chronic hepatitis C (CHC) patients. Iron overload as well as iron deficiency anemia are common clinical findings in these patients. Variceal bleeding is also a common complication. To date, no study has discussed the influence of esophageal bleeding on iron status in anemic CHC bleeders. OBJECTIVE: Was to study reticulocyte hemoglobin content (CHr) and serum hepcidin levels in anemic CHC and to evaluate the influence of variceal bleeding on patients' iron status. METHODS: Serum hepcidin levels and CHr were assessed in 65 early phase CHC patients (20 nonanemic, 23 anemic nonbleeders, and 22 anemic bleeders), and 20 healthy controls; and were compared with the conventional indices of iron deficiency including mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, serum iron, total iron binding capacity, transferrin saturation and ferritin. RESULTS: Hepcidin levels were comparable in patients groups, but were significantly lower in patients than in controls (P = 0.01). Child-Pugh class B patients showed significantly lower hepcidin levels than class A patients. CHr levels were comparable in all groups as well as all iron deficiency indices. Patients with ferritin values or less 100 ng/ml and CHr or less 29 pg/cell or Tfsat or less 16% are more likely to have iron deficiency [odds ratio (OR = 3.93, 95% confidence interval (CI) = 2.54-6.08; OR = 10.50, 95% CI = 1.94-56.55, respectively). CONCLUSION: Esophageal bleeding has an almost no influence on iron status in CHC patients. Serum hepcidin content is influenced by CHC disease rather than by anemia associated with or without esophageal bleeding and it could be used as a marker of early hepatic insufficiency. Assessing CHr content could add a potential utility in the detection of iron deficiency in CHC patients.

Sofosbuvir-containing regimens are safe and effective in the treatment of HCV patients with moderate to severe renal impairment.

BACKGROUND AND AIMS: This study aimed to assess the safety and efficacy of sofosbuvir (SOF)-based regimens in patients with moderate to severe renal impairment; a subject which has been questioned by many investigators with conflicting results. METHODS: This is a real-life multicentre retrospective cohort study on 4944 chronic Hepatitis C virus (HCV) patients with chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m2 ) who received SOF-based therapy in specialized treatment centres affiliated to the National Committee for the Control of Viral Hepatitis in Egypt. The efficacy and safety of SOF-based regimens was assessed. RESULTS: Week 12 virological response rates were 97.5%, 96.7%, 85.7% and 80% in the total cohort, patients with eGFR <30 mL/min/1.73 m2 , patients with associated hepatic decompensation and patients on dialysis respectively. Various treatment regimens did not statistically affect the response rates. Treatment experience, cirrhosis and diabetes were predictors of treatment failure on multivariate analysis. Serious adverse events occurred in 0.1% of cases. Forty patients (0.8%) discontinued treatment. CONCLUSION: Sofosbuvir-based regimens are effective and safe for treating patients with chronic HCV and moderate to severe CKD, and in those with associated hepatic decompensation.