Evolution of liver fibrosis after interferon-based anti-hepatitis C virus therapy failure in 3,049 chronic hepatitis C patients without cirrhosis.

BACKGROUND AND STUDY AIMS: Liver fibrosis is the underlying causeof hepatitis C virus (HCV)-related disease progression to endpoints such as cirrhosis, liver failure, and hepatocellular carcinoma. The aim of our study was to assess changes in hepatic fibrosis in patients with chronic HCV who had a fibrosis evaluation at two time points at least six months apart. PATIENTS AND METHODS: This was a retrospective cohort study that included patients who had failed interferon therapy and received HCV retreatment with direct-acting antivirals (DAAs) at least six months later. Patients were evaluated previously for fibrosis according to liver biopsy and fibrosis biomarkers were evaluated before pegylated interferon and ribavirin (PEG/RBV) therapy. Fibrosis was re-evaluated with fibrosis-4 (FIB-4) scores before starting DAAs. RESULTS: A total of 3,049 patients were included [age 43.47 ± 9.07 years, 55.20 % males] and baseline histopathology showed F1, F2, and F3 in 16.86 %, 46.21 %, and 36.93 %, respectively. The mean time interval between the last dose of previously failed IFN-therapy to the first dose of DAAs was 2.38 (±1.07) years. Overall, there was a significant increase in FIB-4 scores at retreatment times (from 11.71 ± 1.13 to 22.26 ± 1.68, p < 0.001). Patients with baseline FIB-4 < 1.45 (n = 1,569) and between 1.45 and 3.25 (n = 1,237) had significant increases in their FIB-4 at the retreatment time point [median difference; 0.41 (0.91) and 0.24 (1.5), p < 0.001, respectively], whereas patients with FIB-4 > 3.25 had significant reduction of their FIB-4 score at a retreatment timepoint [-0.98 (2.93), p ≤ 0.001]. CONCLUSION: Fibrosis progressed in most patients, even within six months for some patients, and this indicates retreatment of non-system vascular resistance patients even if they do not have significant fibrosis.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with chronic kidney disease.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) prevalence inchronic kidney disease (CKD) patients is significantly higher than in the general population. This study evaluated the efficacy and safety of combined ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with renal impairment. PATIENTS AND METHODS: Our study included 829 patients with normal kidney functions (group 1) and 829 patients with CKD (group 2),which were subdivided into patients not requiring dialysis (group 2a) and those on hemodialysis (group2b). Patients received regimens of ombitasvir/paritaprevir/ritonavir with or without ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks. Clinical and laboratory assessment was done before treatment, and patients were followed up for12 weeks after treatment. RESULTS: The sustained virological response (SVR) at week 12 was significantly higher in group 1 than in the other three groups/subgroups, being 94.2% vs 90.2%, 90%, and 90.7%, respectively. The regimen with the highest SVR was ombitasvir/paritaprevir/ritonavir with ribavirin. The most common adverse event was anemia, which was more common in group 2. CONCLUSION: Ombitasvir/paritaprevir/ritonavir-based therapy in chronic HCV patients with CKD is highly effective, with minimal side effects despite ribavirin-induced anemia.

Tissue Surface Adaptation and Clinical Performance of CAD-CAM Milled versus Conventional Implant-Assisted Mandibular Overdenture.

Purpose: To evaluate the surface adaptation and maximal biting force of CAD-CAM milled mandibular overdenture (CAD-CAM MOD) compared to conventional compression mold mandibular overdenture (CC MOD). Materials and Methods: Ten completely edentulous subjects with persistent complaints of their complete mandibular dentures were received four dental implants in the anterior mandible. Three months after osseointegration, subjects were randomly received either conventional compression mold or CAD-CAM MOD in a crossover design. To assess tissue surface adaptation, the fitting surfaces of each denture base were scanned and placed on the reference master cast. Three and six months after each overdenture was inserted, clinical performance in the form of maximum biting force was evaluated. Results: The results of this study indicated that the tissue surface adaptation of the CAD-CAM MOD bases was significantly better than the conventional (compression mold technique) processed bases where (P=0.0001). Regarding clinical performance (maximum biting force), the CAD-CAM MOD exhibited better clinical performance (P=0.0001). Conclusions: In denture processing methods, the CAD-CAM overdenture delivered more precise adaption and clinical performance than the compression mold technique.

Evaluation of red cell distribution width to platelet ratio as a novel non-invasive index for predicting hepatic fibrosis in patients with chronic hepatitis C.

BACKGROUND AND STUDY AIMS: Assessing the extent of fibrosis is an essential part of therapeutic decisions in patients with chronic hepatitis C (CHC). Liver biopsies are the "gold standard" for evaluating liver fibrosis but have many limitations. Thus, noninvasive predictors of fibrosis have been developed. This study aimed to determine the effectiveness of red cell distribution width (RDW) to platelet ratio as a simple noninvasive method for predicting the hepatic fibrosis stage in patients with CHC. PATIENTS AND METHODS: This cross-sectional study included 197 Egyptian patients with CHC. A routine pretreatment reference needle liver biopsy was performed. Fib-4, transient elastography (TE) by Fibroscan, AST to Platelet Ratio Index (APRI), and RDW to platelet ratio (RPR) were measured. Predictors of significant fibrosis (Metavir score ≥ F2) and advanced fibrosis (Metavir score ≥ F3) were identified. RESULTS: Fib-4, TE, APRI, and RPR values differed significantly when comparing different stages of fibrosis (p < 0.01). Fib-4, TE, APRI, and RPR were reliable diagnostic tools at cutoff values of 1.17, 7.75, 0.18, and 0.07, respectively, for predicting significant fibrosis and cutoff values of 1.99, 8, 1.77, and 0.08, respectively, for predicting advanced fibrosis. Using logistic regression analysis, TE was identified as an independent predictor associated with significant and advanced fibrosis. Fib-4 was significantly associated with advanced fibrosis only. CONCLUSION: The use of Fib-4, TE, APRI, and RPR measurements may decrease the need for liver biopsies for predicting significant and advanced fibrosis. RPR showed fair sensitivity, specificity, positive and negative predictive values, and overall accuracy for predicting significant fibrosis in patients with CHC.

Is urinary ß2-microglobulin a reliable marker for assessment of renal tubular dysfunction in chronic hepatitis B patients receiving tenofovir therapy?

BACKGROUND AND AIM: Urinary ß2-microglobulin (ß2-M) is a marker for renal tubular dysfunction. The current study aimed to assess urinary ß2-M as a reliable marker for early prediction of tenofovir disoproxil fumarate (TDF)-related nephrotoxicity among hepatitis B virus (HBV) patients. METHODS: Forty-two HBV patients who were a candidate for TDF therapy or have recently started it (for less than 6 months) were enrolled and subjected to demographic, clinical, laboratory assessment, abdominal ultrasound and transient elastography. The glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault equation. Also, urinary ß2-M was measured by the ELISA method within 6 months after the introduction of TDF treatment and 6 months later. RESULTS: Mean age was 41.8 (9.55) years, 27 were males and 59.5% of patients have elevated urinary ß2-M after 6 months follow-up of TDF therapy. Urinary ß2-M was 0.07 ± 0.07 µg/ml at baseline and insignificantly increased up to 0.09 ± 0.08 µg/ml after 6 months follow-up. Despite the insignificant increase in serum creatinine from 0.85 ± 0.23 mg/dl at baseline to 0.9 ± 0.21 mg/dl after 6 months and the insignificant decrease in eGFR from 126.2 ± 39.72 ml/min at baseline and 117.64 ± 42.23 ml/min at 6 months follow-up. No correlation was found between the changes in urinary ß2-M and the changes in other renal function indices at baseline and 6 months follow-up. CONCLUSIONS: Short-term TDF therapy is associated with nonsignificant changes either in eGFR or urinary ß2-M; these changes are not clinically relevant that indicates disease progression. Therefore, the suitability of urinary ß2-M as a screening tool for tenofovir induced tubular dysfunction should be further.

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.

Liver stiffness measurements and FIB-4 are predictors of response to sofosbuvir-based treatment regimens in 7256 chronic HCV patients.

Objectives: To assess the role of baseline liver stiffness (LS) by Transient elastography (TE) and FIB-4 in the prediction of virological response to sofosbuvir - based regimens in chronic HCV patients.Methods: A retrospective, multicenter study including 7256 chronic HCV patients who received different sofosbuvir-based regimens. Baseline demographic and laboratory data were recorded. TE was performed with FIB-4 calculation at baseline.Results: Sustained virological response at week 12 post-treatment (SVR12) was 91.4%. Pretreatment TE values and FIB-4 were significantly lower among sustained responders (17.8 ± 11.5 kPa, 2.66 ± 1.98, respectively) versus relapsers (24.5 ± 13.9 kPa, 4.02 ± 3.3, respectively). Best cutoff levels for LS by TE and FIB-4 score for prediction of failure to treatment response were 16.7 kPa and 2.4, respectively. Among different treatment protocol, patients with FIB-4 > 2.4, TE values >16.7 kPa are more prone to treatment failure except when using SOF/SIM treatment regimens.Conclusion: Baseline LS by TE and FIB-4 score may be useful for predicting treatment outcome in the new era of DAAs and could be integrated into pretreatment assessment of chronic HCV patients for better optimization of patient management.

Utility of point shear wave elastography in characterisation of focal liver lesions.

BACKGROUND: The present study aimed at evaluation of the usefulness of point shear wave elastography (pSWE) in characterization of FLL(s) by quantifying their stiffness. METHODS: In total, 197 patients (mean age was 56.57 years) with FLL(s) on conventional ultrasound were included. Final diagnoses, confirmed by imaging and/or biopsy whenever possible, included hepatocellular carcinoma (HCC) (n = 143), metastasis (n = 36), hemangioma (n = 16), and focal nodular hyperplasia (n = 2). Stiffness evaluation was performed by pSWE. Stiffness ratio (lesion to background liver) was calculated. ROC analysis was performed to evaluate the diagnostic accuracy of the stiffness value and stiffness ratio and to extract the optimal cutoff values for characterisation of FLL(s). RESULTS: HCC was significantly softer than its surrounding liver parenchyma [5.43 (3.03) vs. 17.05 (8.53) kPa, p <0.001]. However, the stiffness values for the other examined FLLs were comparable to their surrounding liver parenchyma. No significant difference was detected across different types of metastases or between metastases and surrounding liver (p>0.05). Stiffness ratio was superior to stiffness value in discrimination of HCC from metastasis (AUROC, 0.91 vs. 0.51 respectively). CONCLUSION: pSWE could provide a complementary information about FLLs especially in differentiation between HCCs from metastases.

Interleukin 28B polymorphisms and therapy response in Egyptian hepatitis C genotype-4 patients.

Hepatitis C infection represents a major health problem in Egypt; only 20% of patients undergo spontaneous clearance of the virus and around 25% of all patients progress to develop cirrhosis. More than 90% of Egyptian patients have hepatitis C virus (HCV) genotype-4. Combined pegylated interferon and oral ribavirin are the current standard therapies for HCV-4. The aim of the work is to evaluate the predictive power of the rs12979860 IL28B SNP and rs12980275 IL28B SNP for treatment response in Egyptian patients infected with HCV genotype 4. One hundred eleven HCV patients receiving combined treatment were studied for rs12979860 and rs12980275 polymorphisms by the restriction fragment length polymorphism technique. The rs12979860 CC and rs12979860 AA genotypes were significantly associated with sustained virological response (p=0.001). Our results suggest that studying IL28B polymorphisms contribute to proper prediction of response to standard therapies in Egyptian patients, optimizing cost effectiveness, and minimizing unneeded adverse effect of therapy.

A Possible Role for TNF-α in Coordinating Inflammation and Angiogenesis in Chronic Liver Disease and Hepatocellular Carcinoma.

BACKGROUND: Increasing evidence supports the hypothesis that chronic and persistent inflammation contributes to cancer development. However, the molecular mechanisms that lead to cancer in chronic inflammation and the role of angiogenesis in inflammation-associated cancer remain poorly understood. METHODS: NINETY PATIENTS WERE ENROLLED: 30 cases of CHC without cirrhosis, 28 cases of CHC with liver cirrhosis, and 32 cases of HCC and hepatitis C virus infection. Ten wedge liver biopsies, taken during laparoscopic cholecystectomy, served as normal controls. Serum TNF-α levels were measured using the ELISA technique; in situ hybridization and immunohistochemical studies were used to detect hepatic levels of messenger RNA (mRNA) transcripts and mature protein, respectively, for both TNF-α and VEGF. RESULTS: The highest hepatic expression of TNF-α was noticed in liver cirrhosis specimens compared to noncirrhotic CHC and HCC. Hepatic expression of VEGF and serum level of TNF-α revealed significant increases in the progression of the disease. Moreover, cases with higher grades of inflammation or stages of fibrosis showed significant increases in serum TNF-α and expression of TNF-α and VEGF. Expression of mRNA of both TNF-α and VEGF shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positivity in cases developed HCC. CONCLUSIONS: VEGF signaling could be one of the molecular signaling pathways involved in TNF-α induced angiogenesis which might pose an important link between inflammation and fibrosis in CHC and HCC development and progression. Moreover, serum inflammatory biomarkers can be used to monitor the disease progression.

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.

The Effect of Peginterferon Alpha-2a vs. Peginterferon Alpha-2b in Treatment of Naive Chronic HCV Genotype-4 Patients: A Single Centre Egyptian Study.

BACKGROUND: Egypt has one of the highest (16-8%) prevalence rates of HCV infection in the world. Approximately 90% of Egyptian HCV isolates belong to a single subtype (4a), which responds less successfully to interferon therapy than other subtypes. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naive HCV-infected patients have shown conflicting results. OBJECTIVES: Assessing the effects of Peginterferon alpha-2a versus Peginterferon alpha-2b on the sustained virological response in naive chronic HCV genotype-4 Egyptian patients. PATIENTS AND METHODS: This retrospective study cohort consists of 3718 chronic HCV patients admitted to a large, Egyptian medical center. 1985 patients had been treated with PEG-IFN alfa-2a plus RBV and 1733 patients with PEG-IFN alfa-2b plus RBV between years 2007-2011. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects. RESULTS: The ETR & SVR in patients treated with PEGIFN alfa-2a was 64.1% and 59.6% as compared to treatment with PEGIFN alfa-2b where these parameters were 58.2% and 53.9% respectively (P < 0.05). Treatment discontinuation rates, were similar in the two types of PEGIFN [0.66 (0.37-1.16); P = 0.15]. Significant dose reduction was evident with peginterferon alfa-2b (35.3%) than peginterferon alpha-2a (27.3 %) (P < 0.01). Patients with lower base line AFP and ALT were most likely to achieve SVR using INF alpha 2-a. CONCLUSIONS: Peginterferon alpha-2a has a higher efficacy regarding ETR and SVR as compared to Peginterferon alfa-2b in treatment of naive chronic HCV genotype-4 patients.

Clinical, biochemical and pathological profiles of 5464 Egyptian chronic hepatitis C-infected patients.

BACKGROUND/AIMS: In Egypt, hepatitis C virus (HC is highly endemic with at least 91% are genotype-4. However, HCV-specific burden data for Egypt are scarce. The study aims to identify clinical, biochemical and pathological features of chronic HCV population in Egypt. METHODOLOGY: We analyzed retrospective data of 5,464 HCV-antibody and PCR positive patients attending pre-treatment assessment at one of the National Treatment Centers, Cairo, Egypt. RESULTS: Chronic HCV patients were males (81.4%) in their productive age, mean body mass index (BMI): 28 kg/m2. Laboratory profile demonstrated mean platelet count 214 x 10(3)/µ L with only 14% having thrombocytopenia, amino-transferases were mildly elevated: mean AST, ALT were 56 and 63 respectively,low viraemia: 50% had viral load <100 (x 10(3)) IU/mL,and median AFP level 3.3 ng/mL. Liver biopsy revealed ≤A2 in 92% of patients; 80% had ≤F2 and 7.3 % had F4 according to the METAVIR score. Meta regression demonstrated that advanced stages of fibrosis were significantly correlated with platelet count, AST/ALT ratio, AFP levels and BMI (p <0.001). However there was no correlation with viral load. CONCLUSIONS: To our knowledge, this is the first study on nationwide scale that provided the demographic, biochemical,and histological characteristics for this number of chronic HCV patients presumably genotype-4.