Marwa Khairy

Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4

BACKGROUND & AIMS Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection in the world, and more than 90% of patients are infected with genotype 4 virus. We evaluated the efficacy and safety of the HCV polymerase inhibitor sofosbuvir in combination with ribavirin in HCV genotype 4 patients in Egypt. METHODS Treatment-naïve or treatment-experienced patients with genotype 4 HCV infection (n=103) were randomly assigned to receive either 12 or 24 weeks of sofosbuvir 400 mg and ribavirin 1000-1200 mg daily. Randomization was stratified by prior treatment experience and by presence or absence of cirrhosis. The primary endpoint was the percentage of patients with HCV RNA <25 IU/ml 12 weeks after therapy (SVR12). RESULTS Among all patients, 52% had received prior HCV treatment and 17% had cirrhosis at baseline. SVR12 rates were 90% (46/51) with 24 weeks and 77% (40/52) with 12 weeks of sofosbuvir and ribavirin therapy. Patients with cirrhosis at baseline had lower rates of SVR12 (63% 12 weeks, 78% 24 weeks) than those without cirrhosis (80% 12 weeks, 93% 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events (cerebral ischemia, dyspnea). No adverse events resulted in treatment discontinuation. CONCLUSION Sofosbuvir plus ribavirin for 12 or 24 weeks is effective in treating both treatment-naïve and treatment-experienced Egyptian patients with genotype 4 HCV.

Non-Invasive Prediction of Hepatic Fibrosis in Patients With Chronic HCV Based on the Routine Pre-Treatment Workup

Background Hepatic fibrosis is an inclusion indicator for treatment and a major independent predictor of treatment response in patients with chronic hepatitis C. Liver biopsy, considered as the “gold standard” for evaluating liver fibrosis, has carried some drawbacks. Currently used noninvasive predictors of fibrosis are considered less accurate than liver biopsy. Objectives Our aim was to assess noninvasive predictors of fibrosis in patients with chronic hepatitis C using the routine laboratory pre-treatment workup. Patients and Methods Cross sectional study including 4289 Egyptian patients with chronic hepatitis C were assessed for the need to interferon and ribavirin therapy. Routine pre-treatment workup and reference needle liver biopsy were performed. FIB-4 index, APRI and modified APRI scores were validated. Patients were divided into two groups, first with no or minimal fibrosis, and second with moderate and marked fibrosis using the Metavir score. Results Multivariate logistic regression analysis showed that age, body mass index, aspartate aminotransferase, alpha fetoprotein, platelets count, FIB-4 index, APRI and modified APRI score were significant independent predictors of fibrosis. Age > 43 years, aspartate aminotransferase > 47U/L, platelets < 205×103/mm3, and alpha fetoprotein > 2.6 ng/ml had the highest cutoff points in receiver operator characteristic curves. Taking into account the four variables together; the presence of ≥ 2 variables is associated with moderate and advanced fibrosis with a sensitivity of 0.81, specificity of 0.5, positive predictive value of 0.53 and negative predictive value of 0.79. FIB-4 index represented the best performing receiver operator characteristic curve for diagnosing moderate and marked fibrosis among other independent factors with a sensitivity of 0.74, specificity of 0.6, positive predictive value of 0.56 and negative predictive value of 0.76. Conclusions Chronic HCV pre-treatment routine work up and composite fibrosis scores are good noninvasive predictor of liver fibrosis and can be used as an alternative method to invasive liver biopsy without adding more financial expenses to the treatment.

THE IMPACT OF INTERLEUKIN 28B GENE POLYMORPHISM ON THE VIROLOGICAL RESPONSE TO COMBINED PEGYLATED INTERFERON AND RIBAVIRIN THERAPY IN CHRONIC HCV GENOTYPE 4 INFECTED EGYPTIAN PATIENTS USING DATA MINING ANALYSIS

Background: Chronic HCV represents one of the common causes of chronic liver disease worldwide with Egypt having the highest prevalence, namely genotype 4. Interleukin IL-28B gene polymorphism has been shown to relate to HCV treatment response, mainly in genotype1. Objectives: We aim to evaluate the predictive power of the rs12979860 IL28B SNP and its protein for treatment response in genotype 4 Egyptian patients by regression analysis and decision tree analysis. Patients and Methods: The study included 263 chronic HCV Egyptian patients receiving peg-interferon and ribavirin therapy. Patients were classified into 3 groups; non responders (83patients), relapsers (76patients) and sustained virological responders (104 patients). Serum IL 28 B was performed, DNA was extracted and analyzed by direct sequencing of the SNP rs 12979860 of IL28B gene. Results: CT, CC and TT represented 56 %, 25 % and 19% of the patients, respectively. Absence of C allele (TT genotype) was significantly correlated with the early failure of response while CC was associated with sustained virological response. The decision tree showed that baseline alpha fetoprotein (AFP ≤ 2.68 ng/ml) was the variable of initial split (the strongest predictor of response) confirmed by regression analysis. Patients with TT genotype had the highest probability of failure of response. Conclusions: Absence of the C allele was significantly associated with failure of response. The presence of C allele was associated with a favorable outcome. AFP is a strong baseline predictor of HCV treatment response. A decision tree model is useful for predicting the probability of response to therapy.

Role of Clinical Presentations and Routine CSF Analysis in the Rapid Diagnosis of Acute Bacterial Meningitis in Cases of Negative Gram Stained Smears

Background and Aim. Bacterial meningitis is a lethal, disabling endemic disease needing prompt antibiotic management. Gram stained smears is rapid accurate method for diagnosis of bacterial meningitis. In cases of negative gram stained smears diagnosis is delayed till culture results. We aim to assess the role of clinical presentations and routine CSF analysis in the cost-effective rapid diagnosis of negative gram stained smears bacterial meningitis. Methods. Cross sectional study including 623 acute meningitis patients divided into two groups: bacterial meningitis and nonbacterial meningitis groups. The clinical presentations, systemic inflammatory parameters, and CSF analysis were evaluated and compared in both groups. Results. Altered conscious level, localizing neurological signs, Kernigs and Brudzinskis signs together with peripheral leucocytosis (>10.000/mm3), high CRP (>6) together with high CSF protein (>50 gl/dL), CSF neutrophilic count (≥50% of total CSF leucocytic count), and low CSF glucose level (<45 gm/dL) and CSF/serum glucose ≤0.6 were significantly diagnostic in bacterial meningitis patients. From the significant CSF analysis variables CSF protein carried the higher accuracy of diagnosis 78% with sensitivity 88% and specificity 72%. Conclusions. High CSF protein (>50 mg/dL) together with plasma inflammatory markers and CSF cytochemical parameters can diagnose bacterial meningitis in gram stain negative smear till culture results.

Serum autoantibodies positivity prevalence in patients with chronic HCV and impact on pegylated interferon and ribavirin treatment response.

Prevalence of serum autoantibodies in chronic hepatitis C (HCV) patients is higher than that in the general population. Interferon may induce autoimmune manifestations in patients treated with peg‐interferon and ribavirin. Effect of autoantibody seropositivity and treatment response are limited and controversial.

Egy-score as a noninvasive score for the assessment of hepatic fibrosis in chronic hepatitis C: A preliminary approach

Background and Aims: Egy-Score is a new noninvasive score for prediction of severe hepatic fibrosis in patients with chronic liver diseases. The aim of this study was to validate Egy-Score as a noninvasive score for predicting stage of hepatic fibrosis in a group of Egyptian chronic hepatitis C patients. Patients and Methods: One hundred Egyptian patients with chronic hepatitis C were enrolled. Mean age was 40.25 ± 9.39 years. They were subjected to CA19-9, alpha-2-macroglobulin, total bilirubin, platelet count and albumin, liver biopsy, and histopathological staging of hepatic fibrosis according to METAVIR scoring system as part of their assessment for treatment. Egy-Score was calculated according to the following formula: Egy-Score = 3.52 + 0.0063 × CA19-9 + 0.0203 × age + 0.4485 × alpha-2-macroglobulin + 0.0303 × bilirubin – 0.0048 × platelet – 0.0462 × albumin. Egy-Score results were correlated to the stage of hepatic fibrosis. Results: Egy-Score correlates positively with the stage of hepatic fibrosis (F0–F4). Egy-Score was able to differentiate significant hepatic fibrosis, severe hepatic fibrosis, and cirrhosis accurately. Cutoff values of Egy-Score were 2.91850 (for significant fibrosis), 3.28624 (for severe fibrosis), and 3.67570 (for cirrhosis). Sensitivity, specificity, and areas-under-ROC curve (AUROCs) were 75.8%, 68.42%, and 0.776 (for significant fibrosis “≥F2”), 91.67%, 77.63%, and 0.875 (for severe fibrosis “≥F3”), and 81.82%, 86.52%, and 0.874 (for cirrhosis “F4”), respectively. Conclusion: Egy-Score is a useful noninvasive panel of surrogate biomarkers that could accurately predict different stages of hepatic fibrosis in patients with chronic hepatitis C.

Comparing the efficiency of Fib-4, Egy-score, APRI, and GUCI in liver fibrosis staging in Egyptians with chronic hepatitis C

Assessment of hepatic fibrosis in chronic hepatitis C virus patients by liver biopsy is not widely accepted despite its accuracy, being invasive, carrying complications, and adding cost. This paved the way to development and use of non‐invasive markers of fibrosis in diagnosis of hepatic fibrosis. We aimed at evaluating the efficiency of Fib‐4, Egy‐score, Aspartate‐to‐platelet ratio index (APRI), and Göteborg University Cirrhosis Index (GUCI) in comparison to liver biopsy, in the assessment of hepatic fibrosis in chronic hepatitis C patients. This was a cross sectional study including 200 chronic HCV patients were divided into two groups according to stage of fibrosis (Metavir score) into non‐significant fibrosis (1.27, APRI >0.48, Egy‐score >0.73, and GUCI >0.57 significantly predict significant fibrosis (P < 0.01). Fib‐4 carries the best performance and significant reliability with AUROC 0.783, sensitivity 74%, specificity 69%, PPV 0.55, and NPV 0.86. The addition of BMI to Fib‐4 improved the significant fibrosis AUROC curve performance but did not reach statistical significant improvement. We concluded that age and BMI are good predictors of hepatic fibrosis. Fib‐4 (>1.27) is the best method of prediction of significant fibrosis compared to Egy‐score, APRI, and GUCI. Addition of BMI to Fib‐4 did not improve diagnostic value of Fib‐4.

Effect of treatment with direct acting antivirals on body mass index and hepatic steatosis in chronic hepatitis C

Direct Acting Agents (DAAs) have high cure rate but still lack the knowledge of their effect on hepatic steatosis in chronic hepatitis C (CHC). Controlled Attenuation Parameter (CAP), evaluated with transient elastography, could help in assessment of steatosis grades. We aim to evaluate the effect of DAAs on BMI and steatosis in CHC using CAP. This cohort study included 155 CHC Egyptian patients divided into three groups according to the DAAs regimens. All patients were subjected to pre‐treatment and 3‐months post‐treatment evaluation including BMI, laboratory workup and liver stiffness measurement with simultaneous CAP determination using the (FibroScan®) M probe. Patients mean age was 45.78 ± 11.6 years, 60.6% were females, mean BMI 26.63 ± 2.75 and 18.1% were cirrhotic. Baseline assessment revealed no steatosis in 43.9%, 32.9% had mild‐moderate steatosis and 23.2% had severe steatosis. The overall sustained virological response 12 was 93.6%. Follow‐up revealed stationary steatosis in 56.7% of patients and regression in 21.3%. Mean pre‐treatment CAP were significantly lower in responders 244.9 ± 62.4 dB/m versus non‐responders; 300 ±28.4 dB/m (P = 0.04). ROC curve delineated 273 dB/m as best cutoff for detection of responders with an AUC of 0.801, sensitivity 68.2%, and specificity 100%. BMI significantly increased after treatment (P = 0.004) particularly in patients with worsened steatosis (P = 0.001). Steatosis significantly correlated with BMI (r = 0.3, P value = < 0.001). DAAs causes a significant change in steatosis grade in a subset of treated patients. Pretreatment CAP was significantly lower in responders. BMI significantly increases following treatment particularly in patients with worsened steatosis.

Validation of Hepa-index as a non-invasive biomarkers panel for assessment of hepatic fibrosis in Egyptians with chronic hepatitis C

Objectives: To validate the diagnostic performance of Hepa-Index in predicting different stages of hepatic fibrosis in Egyptian patients with chronic hepatitis C (CHC). Methods: Hundred treatment naïve chronic hepatitis C Egyptian patients were prospectively enrolled between June 2014 and January 2015. They were subjected to: platelet count, alpha-2-macroglobulin (α2-MG), total bilirubin, gamma glutamyl transpeptidase (GGT), total cholesterol, liver biopsy and histopathological staging of hepatic fibrosis according to METAVIR scoring system. Hepa-Index was calculated according to the formula: Hepa-Index=exp (-0.021 x platelet +1.65 x α2-MG+0.2 x total bilirubin + 0.026 x GGT -1.215 x total cholesterol) / (1+exp (-0.021 x platelet + 1.65 x α2-MG + 0.2 x total bilirubin +0.026 x GGT -1.215 x total cholesterol). Results: Hepa-Index correlates positively with the stage of hepatic fibrosis. Cut off values of Hepa-Index were: 0.2 for predicting significant hepatic fibrosis (≥F2 METAVIR), 0.3 for severe hepatic fibrosis (≥F3 METAVIR) and 0.4 for cirrhosis (F4 METAVIR). Hepa-Index was able to detect significant fibrosis with sensitivity of 69.4%, specificity of 76.3% and AUROC of 0.803. Hepa-Index was also able to detect severe hepatic fibrosis with sensitivity of 79.2%, specificity of 64.5% and AUROC of 0.783 and cirrhosis with sensitivity of 81.8%, specificity of 68.5% and AUROC of 0.744. Conclusion: Hepa-Index is a good non-invasive biomarkers panel that can be used for non-invasive assessment of hepatic fibrosis in chronic hepatitis C patients.

Single Nucleotide rs760370 Polymorphism at the Main Ribavirin Transporter Gene Detection by PCR-RFLP Assay Compared with the TaqMan Assay and Its Relation to Sustained Virological Response in Chronic HCV Patients Treated with Pegylated Interferon–Ribavirin Therapy

Ribavirin clearly plays a role in chronic hepatitis C treatment response. The equilibrative nucleoside transporter-1 codified by SLC29A1 gene has been associated with ribavirin uptake into hepatocytes and erythrocytes. rs760370A>G single nucleotide polymorphism (SNP) at the SLC29A1 gene may have a role in ribavirin-based regimen treatment response. Accuracy of the polymerase-chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay compared with the TaqMan assay for the detection of the SNP rs760370 at the main ribavirin transporter gene and its relation to sustained virological response in chronic hepatitis C virus (HCV) patients treated with pegylated interferon-ribavirin therapy. The study included 100 chronic HCV patients who were treated with pegylated interferon-ribavirin therapy. The patients were categorized according to the treatment response into responders (50 patients) and null responders (50 patients). rs760370 SNP was measured using TaqMan 5-nuclease assay and by the newly developed PCR-based RFLP assay. The overall accuracy of the newly developed PCR-RFLP assay compared with the TaqMan assay for rs760370 polymorphism detection was 100%. Allelic frequencies at rs760370 were as follows: A/A genotype (28%), A/G genotype (58%), and G/G genotype (14%). Treatment response was not significantly related with rs760370 polymorphism (P = 0.5). Ribavirin-induced anemia was good predictor of sustained virological response (P = 0.001), but was not related to rs760370 polymorphism (P = 0.92). PCR-RFLP assay is an accurate, cost-effective method in the detection of rs760370 compared with TaqMan assay. rs760370 SNP cannot serve as predictor of response in chronic HCV patients treated with interferon ribavirin therapy.