Asmaa Gomaa

Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide and, owing to changes in the prevalence of the two major risk factors, hepatitis B virus and hepatitis C virus, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed world. Early diagnosis remains the key to effective treatment and there have been recent advances in both the diagnosis and therapy of HCC, which have made important impacts on the disease. This review outlines the epidemiological trends, risk factors, diagnostic developments and novel therapeutics for HCC, both in the developing and developed world.

Urinary Metabolic Biomarkers of Hepatocellular Carcinoma in an Egyptian Population: A Validation Study

The advent of metabonomics has seen a proliferation of biofluid profiling studies of patients with hepatocellular carcinoma. The majority of these studies have been conducted in single indigenous populations making the widespread applicability of candidate metabolite biomarkers difficult. Presented here is a urinary proton nuclear magnetic resonance spectroscopy study of mainly hepatitis C virus infected Egyptian patients with hepatocellular carcinoma, which corroborates findings of a previous study from our group of mainly hepatitis B-infected Nigerian patients with hepatocellular carcinoma. Using multivariate statistical analysis, in the form of orthogonal signal-corrected partial least squared discriminant analysis, the sensitivity and specificity of the technique for distinguishing patients with tumors from healthy controls and patients with cirrhosis was 100%/94% and 81%/71%, respectively. Discriminatory metabolites included glycine, trimethylamine-N-oxide, hippurate, citrate, creatinine, creatine, and carnitine. This metabolic profile bears similarity to profiles identified in the Nigerian cohort of subjects indicative of tumor effects on physiology, energy production, and aberrant chromosomal methylation. This is the first study to identify similarly altered urine metabolic profiles of hepatocellular carcinoma in two etiologically and ethnically distinct populations, suggesting that altered metabolism as a result of tumorogenesis is independent of these two factors.

Comparing staging systems for predicting prognosis and survival in patients with hepatocellular carcinoma in Egypt.

Introduction Several hepatocellular carcinoma (HCC) staging systems are available. Although the European Association for Study of Liver Diseases (EASL) and American Association for the Study of Liver Diseases (AASLD) recommended the use of Barcelona Clinic Liver Cancer (BCLC), many studies in different populations revealed heterogeneous results. The aim of this study was to compare different staging systems for predicting prognosis and survival, and for stratifying HCC patients for treatment at a national referral centre for liver disease in Egypt. Methods 2000 Patients were included in this study. Baseline demographic, clinical, laboratory, and radiological data were determined at diagnosis. Patients were stratified using the Okuda, BCLC, Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS). Patients’ survival in different stages within each staging system and the validity of the system in predicting survival were compared. Results The overall survival was 15 months. The 1-, 2-, 3- and 4-year survival of the entire cohort was 56%, 34%, 25% and 15% respectively. The presence of ascites, multiple focal lesions, large tumour size >5 cm, portal vein thrombosis, extra-hepatic spread, AFP≥200 ng/ml and poor Child score were independent predictors of survival (p<0.001). All staging systems were significant in determining overall survival in univariate and multivariate analyses. BCLC was the most predictive staging system for the whole cohort (p<0.001). Among the subgroup of patients offered potentially curative therapy, BCLC was the most informative system in predicting patient survival (p<0.001). For patients with advanced HCC not amenable for specific therapy, CLIP was the best staging system for predicting prognosis (p<0.001). Conclusion BCLC staging system provided the best prognostic stratification for HCC patients. However, CLIP score has the highest stratification ability in patients with advanced HCC highlighting the importance of including AFP in best staging system.

Hepatitis C in Egypt – past, present, and future

Hepatitis C viral infection is endemic in Egypt with the highest prevalence rate in the world. It is widely accepted that the implementation of mass population antischistosomal treatment involving administration of tartar emetic injections (from 1950s to 1980s) led to widespread infection. What is less well known, however, is that these schemes were implemented by the Egyptian Ministry of Health on the advice of the World Health Organization. There has been a spectrum of treatments to target the public health disaster represented by the hepatitis C problem in Egypt: from the use of PEGylated interferon to the recent use of direct acting antiviral drugs. Some new treatments have shown >90% efficacy. However, cost is a key barrier to access these new medicines. This is coupled with a growing population, limited resources, and a lack of infection control practices which means Egypt still faces significant disease control issues today.

Hepatitis C infection in Egypt: prevalence, impact and management strategies

Hepatitis C virus (HCV) infection is a major public health burden in Egypt, where it bears the highest prevalence rate in the world. Estimates for prevalence are based upon data reported from the 2008 and 2015 Egypt Demographic Health Surveys. In this review, we demonstrate the prevalence results of both surveys and analyze the difference in the results. The overall HCV prevalence is estimated to be declining. However, the clinical impact of chronic HCV infection is expected to grow considerably. A mathematical model shows that by increasing the rate of treatment, the expected number of patients will decline significantly in 2030. The current and expected future burden of chronic HCV infection to the Egyptian economy, including direct and indirect costs due to disability and loss of lives, has been estimated and discussed in this review. The economic burden will continue to grow, but a model shows that the introduction of highly effective therapies will result in a significant reduction in the cumulative total economic burden of HCV by 2030. In recognition of the HCV tremendous health and economic burden, the Egyptian government established the National Committee for Control of Viral Hepatitis to implement an integrated nationwide strategy to provide patient care and ensure global treatment access. This review illustrates the epidemiological and disease burden aspects of HCV in Egypt in addition to introducing the national plan and program for managing HCV, which has been successful so far in treating a large number of patients, with the aim of achieving disease control and eventual elimination in Egypt.

Hepatitis C treatment: where are we now?

Chronic hepatitis C infection affects millions of people worldwide and confers significant morbidity and mortality. Effective treatment is needed to prevent disease progression and associated complications. Previous treatment options were limited to interferon and ribavirin (RBV) regimens, which gave low cure rates and were associated with unpleasant side effects. The era of direct-acting antiviral (DAA) therapies began with the development of first-generation NS3/4A protease inhibitors in 2011. They vastly improved outcomes for patients, particularly those with genotype 1 infection, the most prevalent genotype globally. Since then, a multitude of DAAs have been licensed for use, and outcomes for patients have improved further, with fewer side effects and cure rates approaching 100%. Recent regimens are interferon-free, and in many cases, RBV-free, and involve a combination of DAA agents. This review summarizes the treatment options currently available and discusses potential barriers that may delay the global eradication of hepatitis C.

Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion

Background:Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI).Methods:In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival.Results:Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI.Conclusions:The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown.

Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma.

BACKGROUND AND AIM NK-cells are the principle defense line against different malignancies. Their activation status is determined by the balance between activating and inhibitory receptors such as NKG2D and NKG2A, respectively. MicroRNAs are crucial post-transcriptional regulators of gene expression, playing key roles in modulating NK-cell development and function. The aim of this study is to investigate the role of miRNAs in regulating the activation and cytotoxic function of NK-cells in HCC. METHODS In silico analysis was performed to predict a potential miRNA that might target NKG2D and NKG2A mRNAs. NK-cells were isolated from HCC patients and healthy controls, after which miRNA and mRNA were quantified. Manipulating miRNA expression was performed followed by investigating downstream targets and the cytotoxic activity of NK-cells against Huh-7 cell lines. RESULTS NK-cells of HCC patients showed miR-182 overexpression compared to controls. NKG2D and NKG2A were upregulated and downregulated, respectively, in HCC NK-cells. Upon forcing miR-182 expression in the HCC NK-cells, upregulation of both receptors was observed. Finally, miR-182 was reported to induce NK-cell cytotoxicity represented in Perforin-1 upregulation and increase in cytolytic killing of co-cultured Huh-7 cells. CONCLUSION Our findings suggest that miR-182 may augment NK-cell cytotoxicity against liver cancer via modulating NKG2D and NKG2A expressions.

MiR-615-5p depresses natural killer cells cytotoxicity through repressing IGF-1R in hepatocellular carcinoma patients

Abstract miR-615-5p was characterized by our group as a tumour suppressor. IGF-1 R activates a downstream signalling pathway, well characterized in liver cells, however, its role in immunity especially Natural Killer cells (NKs) remains vague. This study aimed at investigating the regulatory role of miR-615-5p on IGF signalling and its impact on NKs cytotoxicity in HCC. Our results showed an upregulation in miR-615-5p and IGF-1 R in NKs of 130 HCC patients compared to 35 controls. Forcing the expression of miR-615-5p, repressed IGF-IR, attenuated NKs cytotoxicity, decreased CD56dim, increased CD56bright NK subsets and reduced the cytotoxic markers NKG2D, TNF-α and perforins. It repressed NKG2D ligand (ULBP2) in Huh-7 cells. In conclusion, miR-615-5p represses IGF-1 R in NKs and their target hepatocytes; however, it has a contradicting impact on HCC progression on both cell types. These findings might pave the way for better understanding the role of microRNAs in NKs function and HCC immune-pathogenesis.

Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4

BACKGROUND & AIMS Although treatment of hepatitis C virus (HCV) and HCV-genotype-4 (GT4) has become very effective, it remains very expensive, and affordable options are needed, especially in limited resource countries. The aim of this study was to assess the efficacy and safety of the combination of ravidasvir (an NS5A inhibitor) and sofosbuvir to treat patients with chronic HCV-GT4 infection. METHODS A total of 300 patients with HCV-GT4 infection were recruited in three groups: treatment-naïve patients with or without compensated Child-A cirrhosis (Group 1); interferon-experienced patients without cirrhosis (Group 2); and interferon-experienced patients with cirrhosis (Group 3). Groups 1 and 2 received ravidasvir 200 mg QD plus sofosbuvir 400 mg QD for 12 weeks and were randomized 1:1 to treatment with or without weight-based ribavirin. Group 3 patients received ravidasvir plus sofosbuvir with ribavirin and were randomized 1:1 to a treatment duration of 12 weeks or 16 weeks. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12). RESULTS A total of 298 patients were enrolled: 149 in Group 1, 79 in Group 2 and 70 in Group 3. SVR12 was achieved in 95.3% of all patients who started the study, including 98% of patients without cirrhosis and 91% of patients with cirrhosis, whether treatment-naïve or interferon-experienced. Ribavirin intake and history of previous interferon therapy did not affect SVR12 rates. No virologic breakthroughs were observed and the study treatment was well tolerated. CONCLUSIONS Treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high sustained virologic response rate for HCV-GT4 infected patients with and without cirrhosis, regardless of previous interferon-based treatments. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT02371408. LAY SUMMARY This study evaluated efficacy and safety of the new oral hepatitis C drug ravidasvir in combination with the approved oral drug sofosbuvir in 298 patients infected with hepatitis C type 4. Our results showed that treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high response rate in patients with and without cirrhosis.