Ashraf Omar Abdelaziz

Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt

The distribution of hepatitis C virus (HCV) genotypes was evaluated in individuals with hepatocellular carcinoma (HCC) and cirrhosis in Egypt. A total of 206 patients sero‐positive for HCV‐RNA among 400 surveyed individuals (186 with HCC, 100 with cirrhosis, and 114 healthy volunteers) were analyzed for HCV genotype. Of 206 patients, 129 had HCC, 65 had cirrhosis without HCC, and 12 were healthy volunteers. Phylogenetic analysis of sequence showed that of 206 samples, 186 contained HCV genotype 4 (90.3%), while 20 had HCV genotype 1 (9.7%). Among subjects with genotype 4, subtype 4a was predominant (79%), other subtypes included 4d, 4m, 4n, and 4o. Among those with HCV genotype 1, 15 had subtype 1g and five subtype 1a. Although subtype 4a was noted slightly more frequently in HCC (76%) compared to cirrhosis (66%) and controls (50%), there was no statistically significant difference between these three groups (P = 0.08). In conclusion, HCV genotype 4 predominates in Egypt. There was no association between subtypes of genotype 4 and the development of HCC. J. Med. Virol. 81:844–847, 2009.

Survival and Prognostic Factors for Hepatocellular Carcinoma: an Egyptian Multidisciplinary Clinic Experience

BACKGROUND Hepatocellular carcinoma (HCC) is a dismal tumor with a high incidence, prevalence and poor prognosis and survival. Management of HCC necessitates multidisciplinary clinics due to the wide heterogeneity in its presentation, different therapeutic options, variable biologic behavior and background presence of chronic liver disease. We studied the different prognostic factors that affected survival of our patients to improve future HCC management and patient survival. MATERIALS AND METHODS This study is performed in a specialized multidisciplinary clinic for HCC in Kasr El Eini Hospital, Cairo University, Egypt. We retrospectively analyzed the different patient and tumor characteristics and the primary mode of management applied to our patients. Further analysis was performed using univariate and multivariate statistics. RESULTS During the period February 2009 till February 2013, 290 HCC patients presented to our multidisciplinary clinic. They were predominantly males and the mean age was 56.5 ± 7.7 years. All cases developed HCC on top of cirrhosis that was mainly due to HCV (71%). Most of our patients were Child-Pugh A (50%) or B (36.9%) and commonly presented with small single lesions. Transarterial chemoembolization was the most common line of treatment used (32.4%). The overall survival was 79.9% at 6 months, 54.5% at 1 year and 22.4% at 2 years. Serum bilirubin, site of the tumor and type of treatment were the significant independent prognostic factors for survival. CONCLUSIONS Our main prognostic variables are the bilirubin level, the bilobar hepatic affection and the application of specific treatment (either curative or palliative). Multidisciplinary clinics enhance better HCC management.

Microwave ablation versus transarterial chemoembolization in large hepatocellular carcinoma: prospective analysis.

Abstract Objective. Limited therapies are offered for large hepatocellular carcinoma (HCC). It carries dismal prognosis and efforts tried changing its management from a palliative to a curative mode. Transarterial chemoembolization (TACE) is a palliative procedure that may have survival benefit if compared to non-management of large lesions. Microwave ablation (MWA) has emerged as a relatively new technique with promise of larger and faster ablation. We aim to evaluate the efficacy and safety of percutaneous MWA versus TACE for large tumors (5–7 cm) and to assess their effects on local tumor progression and survival. Patients and methods. Sixty-four patients with large lesions are managed in our multidisciplinary HCC clinic and were divided into two groups treated either by MWA or TACE. Complete response rate, local recurrence, de novo lesions, and overall survival analysis are compared between both procedures. Results. Both groups were comparable as regards the demographic and ultrasonographic features. MWA showed higher rates of complete ablation (75%) with fewer sessions, lower incidence of tumor recurrence (p = 0.02), development of de novo lesions (p = 0.03), occurrence of post-treatment ascites (p = 0.003), and higher survival rates (p = 0.04). The mean survival of the microwave group was 21.7 months with actuarial probability of survival at 12 and 18 months 78.2% and 68.4%, respectively. The mean survival of the TACE group was 13.7 months with actuarial probability of survival at 12 and 18 months being 52.4% and 28.6%, respectively. Conclusion. MWA showed better results than TACE in the management of large HCC lesions.

Planning and prioritizing direct-acting antivirals treatment for HCV patients in countries with limited resources: Lessons from the Egyptian experience

BACKGROUND AND AIMS The introduction of direct-acting antivirals for hepatitis C virus (HCV) in Egypt led to massive treatment uptake, with Egypts national HCV treatment program becoming the largest in the world. The aim of this paper is to present the Egyptian experience in planning and prioritizing mass treatment for patients with HCV, highlighting the difficulties and limitations of the program, as a guide for other countries of similarly limited resources. METHODS Baseline data of 337,042 patients, treated between October 2014 to March 2016 in specialized viral hepatitis treatment centers, were grouped into three equal time intervals of six months each. Patients were treated with different combinations of direct-acting antivirals, with or without ribavirin and pegylated interferon. Baseline data, percentage of patients with known outcome, and sustained virological response at week 12 (SVR12) were analyzed for the three cohorts. The outcomes of 94,258 patients treated in the subsequent two months are also included. RESULTS For cohort-1, treatment was prioritized for patients with advanced fibrosis (F3-F4 fibrosis, liver stiffness ≥9.5 kPa, or Fibrosis-4 ≥3.25). Starting cohort-2, all stages of fibrosis were included (F0-F4). The prioritization strategy in the initial phase caused delays in enrollment and massive backlogs. Cohort-1 patients were significantly older, and more had advanced fibrosis compared to subsequent cohorts. The percentage of patients with known SVR12 results were low initially, and increased with each cohort, as several methods to capture patient results were adopted. Sofosbuvir-ribavirin therapy for 24 weeks had the lowest SVR12 rate (82.7%); while other therapies were associated with SVR12 rates between 94% and 98%. CONCLUSION Prioritization based on fibrosis stage was not effective and enrollment increased greatly only after including all stages of fibrosis. The availability of generic drugs reduced costs, and helped massively increase uptake of the program. Post-treatment follow-up was initially very low, and although this has increased, further improvement is still needed. LAY SUMMARY We are presenting the largest national program for HCV treatment in the world. We clearly demonstrate that hepatitis C can be cured efficiently in large scale real-life programs. This is a clear statement that global HCV eradication is foreseeable, providing a model for other countries with limited resources and prevalent HCV. Moreover, the availability of generic products has influenced the success of this program.

The pattern of transmission transfusion virus infection in Egyptian patients

The natural history of transmission transfusion virus (TTV) infection has not been precisely delineated. Previously published data show that TTV infection may be acquired early in life, particularly in countries with high prevalence rates in the general population.’ It was shown that TTV infection is present worldwide among blood donors, ranging from 1% in Taiwan, to 62% in Brazil.’ In Egypt, the reported incidence is 29%.2 The incidence of TTV in different liver diseases is also variable: 2946% in acute hepatitis, 47-71% in chronic hepatitis, 9.2-30% in hepatocellular carcinoma (HCC), and 63% in patients with cirrhosis.’ However, TTV has also been found in association with many other diseases, such as bilharziasis,* renal failure (RF), and beta-thalassemia,3 and in patients exposed to repeated blood transfusion4 However, the significance of this viral association is not yet clarified yet. Therefore, the present study was conducted to determine the pattern of TTV infection in six groups of Egyptian patients with HCC, bilharziasis, hepatitis C virus (HCV)-associated chronic active hepatitis (CAH), Hodgkin’s disease (HD), RF and diabetes mellitus (DM), in addition to a group of healthy blood donors (HBDs) negative for both hepatitis B virus (HBV) and HCV. The study included six groups of patients (n=204) -37 HCC, 30 RF, 30 HD, 30 DM (22 non-insulindependent DM (NIDDM) and eight insulin-dependent DM (IDDM)), 30 CAH with HCV and 47 bilharziasis patients-who attended the National Cancer Institute, Cairo University, Ain Shams University Hospital and Theodore Bilhars Institute during 1998-2000. Also, 31 HBDs negative for all HBV and HCV markers were included.

Disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma is associated with repression of interferon regulatory factor-1.

Background/aim Infection with hepatitis C virus (HCV) frequently results in a persistent infection, suggesting that it has evolved efficient mechanism(s) for blocking the host cells innate antiviral response. The immune response to virus infection results in activation or direct induction of the interferon regulatory factors (IRFs), which are a family of proteins involved in the regulation of interferon (IFN) and IFN inducible genes. IRF-3 and IRF-7 have been shown to play an essential role in virus-dependent signaling, whereas IRF-1 is critical for proper IFN-dependent gene expression. This study has been performed to show the expression profile of IRF-1, IRF-3, and IRF-7 in Egyptian patients with HCV-related liver diseases and hepatocellular carcinoma (HCC). Materials and methods This study included 90 patients, who were positive for HCV infection by reverse transcription PCR, divided into three groups: group I (Gr I) included 30 patients with chronic hepatitis C, group II (Gr II) included 30 patients with liver cirrhosis in addition to group III (Gr III) of 30 patients with HCC. Reverse transcription PCR analysis was performed to determine the expression profile of IRF-1, IRF-3, and IRF-7 genes extracted from the peripheral blood mononuclear cells of those patients. Results IRF-1expression was significantly higher (P<0.001) in patients of Gr I (86.6%) compared with those in Gr II (46.7%) and Gr III (36.7%), whereas IRF-3 expression was significantly higher (P<0.005) among patients of Gr II (73.3%) in comparison with that in Gr I (50%) and Gr III (36.7%). In contrast, although expression of IRF-7 was higher in Gr II than in the other groups, there was no statistically significant difference (P > 0.05). Conclusion Alterations in IRFs expression might be considered as markers associated with a higher risk of cirrhosis in patients with chronic HCV infection. Expression of IRF-1 and IRF-3 were more prevalent in patients with chronic HCV and cirrhosis, respectively, in comparison with HCC patients. Thus, IRF-1 could be nominated as one of the tumor suppressor factors and could aid in the early detection of HCC.

Dynamic interplay between CXCL levels in chronic Hepatitis C patients treated by Interferon

BackgroundCombined pegylated interferon-α and ribavirin therapy has sustained virological response (SVR) rates of 54% to 61%. Pretreatment predictors of SVR to interferon therapy have not been fully investigated yet. The current study assesses a group of chemokines that may predict treatment response in Egyptian patients with chronic HCV infection.Patients and methodsCXCL5, CXCL9, CXCL11, CXCL12, CXCL 13, CXCL 16 chemokines and E-Cadherin were assayed in 57 chronic HCV patients’ sera using quantitative ELISA plate method. All studied patients were scheduled for combined pegylated interferon alpha and ribavirin therapy (32 patients received pegylated interferon α 2b, and 25 patients received pegylated interferon α 2a). Quantitative hepatitis C virus RNA was done by real time RT-PCR and HCV genotyping by INNOLIPAII.ResultsThere was no significant difference (p > 0.05) in baseline HCV RNA levels between responders and non-responders to interferon. A statistically significant difference in CXCL13 (p = 0.017) and E-Cadherin levels (P = 0.041) was reported between responders and nonresponders at week 12. Significant correlations were found between changes in the CXCL13 levels and CXCL9, CXCL16, E-cadherin levels as well as between changes in E-cadherin levels and both CXCL16 and ALT levels that were maintained during follow up. Also, significant changes have been found in the serum levels of CXCL5, CXCL13, and CXCL16 with time (before pegylated interferon α 2 a and α 2 b therapy, and at weeks 12 and 24) with no significant difference in relation to interferon type and response to treatment.ConclusionSerum levels of CXCL13 and E-Cadherin could be used as surrogate markers to predict response of combined PEG IFN-α/RBV therapy, especially at week 12. However, an extended study including larger number of patients is needed for validation of these findings.Clinical trial NoNCT01758939

The Core/E1 domain of hepatitis C virus genotype 4a in Egypt does not contain viral mutations or strains specific for hepatocellular carcinoma

BACKGROUND Hepatitis C virus (HCV) infection is a well-documented etiological factor for hepatocellular carcinoma (HCC). As HCV shows remarkable genetic diversity, an interesting and important issue is whether such a high viral genetic diversity plays a role in the incidence of HCC. Prior data on this subject are conflicting. OBJECTIVES Potential association between HCV genetic mutations or strain variability and HCC incidence has been examined through a comparative genetic analysis merely focused on a single HCV subtype (genotype 4a) in a single country (Egypt). STUDY DESIGN The study focused on three HCV sequence datasets with explicit sampling dates and disease patterns. An overlapping HCV Core/E1 domain from three datasets was used as the target for comparative analysis through genetic and phylogenetic approaches. RESULTS Based on partial Core/E1 domain (387 bp), genetic and phylogenetic analysis did not identify any HCC-specific viral mutations and strains, respectively. CONCLUSIONS The Core/E1 domain of HCV genotype 4a in Egypt does not contain HCC-specific mutations or strains. Additionally, sequence errors resulting from the polymerase chain reaction, together with a strong evolutionary pressure on HCV in patients with end-stage liver disease, have significant potential to bias data generation and interpretation.

De-novo versus recurrent hepatocellular carcinoma following direct-acting antiviral therapy for hepatitis C virus

Introduction A recent appearance of direct-acting antivirals (DAAs) led to a surge in hepatitis C virus (HCV) management. Nowadays, a large proportion of treated patients have cirrhosis with a retained possibility to develop hepatocellular carcinoma (HCC) even after complete cure. We aimed to study tumoral differences between patients who developed HCC after DAAs as either a recurrence or de-novo HCC. Methods We retrospectively analyzed 89 patients who presented to our HCC multidisciplinary clinic with HCC lesions following DAA therapy. A total of 45 patients had complete response to HCC according to the modified Response Evaluation Criteria in Solid Tumors before DAAs intake. Another 44 patients developed de-novo lesions after DAA treatment. Both groups were compared regarding their baseline characteristics, tumor criteria, response to DAAs as well response to HCC treatment. Results Both groups showed no significant difference regarding their baseline characteristics (age, sex, Child–Pugh score, and performance status) or response to DAAs (P=0.5). No significant difference was present between groups according to number, site, and size of lesions. However, time elapsed between the end of DAAs therapy and first diagnosis of HCC was significantly longer in de-novo group (15.22±16.39 months) versus recurrence group (6.76±5.1 months) (P=0.008). In addition, response to ablation was significantly better in de-novo lesions compared with recurrent HCC (P=0.03). Conclusions Although de-novo HCC lesions significantly developed later than recurrent lesions in DAAs-treated patients, their response rates were significantly better. No differences were detected between both groups in their response to DAAs and their tumoral characteristics.

Interferon-γ and Interleukin-10 Gene Polymorphisms are not Predictors of Chronic Hepatitis C (Genotype-4) Disease Progression.

Immunoregulatory cytokines have an influence on hepatitis C virus (HCV) infection outcome. This study aimed to determine whether single nucleotide polymorphisms (SNP) in IFN- γ and IL-10 genes are associated with susceptibility and/or are markers of prognosis regarding chronic hepatitis C outcomes. IFN γ (+874T/A) and IL-10 (-1082G/A) genotypes were determined in 75 HCV genotype 4 patients with different disease severities (chronic hepatitis, n=25, liver cirrhosis and hepatocellular carcinoma (HCC) on top of liver cirrhosis, n=50) and 25 healthy participants using allele-specific polymerase chain reaction. No statistical differences in allele or genotype distributions of IFN γ and IL-10 genes were detected between patients and controls or between patientgroups. No significant difference in the frequency of IL-10 SNP at position -1082 or IFN-γ at position +874T/A was found between chronic HCV genotype 4 and with progression of disease severity in liver cirrhosis or HCC. In conclusion; interferon-γ and interleukin-10 gene polymorphisms are not predictors of disease progression in patients with chronic hepatitis C (Genotype-4).