Moutaz Derbala

Interleukin-28 and hepatitis C virus genotype-4: Treatment-induced clearance and liver fibrosis

AIM To investigate the association between interleukin-28B (IL28B) genotype and response to treatment and hepatic fibrosis in patients with hepatitis C virus (HCV) genotype 4. METHODS Two hundred and one HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. End of treatment response (ETR) was defined as loss of detectable serum HCV RNA at the end of treatment. Sustained viral response (SVR) was defined as loss of detectable serum HCV RNA at the end of 24 wk follow up. Genotyping of IL28B rs12979860 was performed using the TaqMan assay. We used logistic regression to estimate the adjusted odds ratio (aOR) and 95%CI. RESULTS The study included 201 HCV-genotype 4 patients. The majority of patients were men (89.6%), with a median age of 47 years, inter-quartile range (40-51). Approximately 62.5% of patients had ETR, and 49.6% had SVR. Individuals who achieved SVR were more likely to be younger (χ(2) = 4.91, P = 0.027), and less likely to have fibrosis (χ(2) = 15.54, P < 0.0001), or inflammation (χ(2) = 7.58, P = 0.006). The genotype distribution of rs12979860 was 36.2%, 49.0% and 14.8% for genotypes CC, CT, and TT, respectively. In these participants, rs12979860 genotype distribution did not differ by gender (P = 0.466), pretreatment viral load (P = 0.600), inflammation (P = 0.435), or fibrosis (P = 0.291). The frequencies of IL28B rs12979860 genotypes were TT (14.8%), CT (49.0%), and CC (36.2%). Compared to rs12979860 genotype TT, aORs (95%CI) for ETR and SVR were: CC genotype, [17.55 (5.34-57.69) and 5.92 (2.09-16.76), respectively]; CT genotype, [5.15 (1.80-14.78) and 2.48 (0.94-6.52), respectively]. In the current study, the patients who did not achieve ETR or SVR had a lower prevalence of rs12979860 CC (17.4% and 23.3%, respectively) than individuals who had ETR or SVR (47.9% and 47.2%, respectively). Individuals with rs12979860 CC genotype had approximately 6 times the odds of SVR compared to individuals with TT genotype (aOR = 5.92; 95%CI: 2.09-16.76). Similarly, patients with CT genotype had SVR more often than patients with TT genotype (aOR = 2.48; 95%CI: 0.94-6.52). Carrying at least one copy of the C allele (genotypes CT and CC) had almost 8 times the probability of ETR compared to those with genotype rs12979860 TT (aOR = 7.87; 95%CI: 2.84-21.82), and approximately 3 times the odds of SVR compared to those with genotype rs12979860 TT (aOR = 3.46; 95%CI: 1.37-8.74). In addition, data were consistent with a significant gene-dose relationship (aOR = 4.05/allele; 95%CI: 2.27-7.22). The association between rs12979860 genotype and SVR was similar among those who achieved and those who did not achieve SVR. CONCLUSION In HCV-genotype 4 patients, rs12979860 is a sensitive predictor of viral clearance, independent of viral load, age, gender or fibrosis, with no similar relation to severity of fibrosis.

Viral kinetic of HCV genotype‐4 during pegylated interferon alpha 2a: ribavirin therapy

Summary.  Kinetics of hepatitis C virus (HCV) during pegylated interferon (PEG‐IFN) and early monitoring of viral decline were recently described to predict treatment outcomes and in turn reduce the course of treatment, adverse effects and cost. However, there is limited (if any) information on the viral dynamics of HCV‐4. Our aim is to follow the HCV‐RNA kinetics during PEG‐IFN alpha 2a and ribavirin therapy and the best time for predicting sustained viral response (SVR) in genotype‐4 patients. Serum HCV‐RNA levels before initial dosing (baseline level) and at 24 h, week 1, week 4, week 12, week 24, week 48 and week 72 were assessed in 84 HCV genotype‐4 patients treated weekly by PEG‐IFN alpha 2a and daily ribavirin. At the end of treatment, out of the 84 treated patients, 19 (22.6%) were non‐responders while 65 (77%) showed end‐of‐treatment response (ETR). However, 8 patients relapsed (9.5%), thus the SVR was observed in 57 patients (67.9%). Younger patients were more likely to attain SVR, where the odds of SVR increased by a factor of 0.94 for each year increase in age (95% CI: 0.90–0.99, P = 0.019). Although a significant negative correlation between stage of fibrosis and rate of viral decline at weeks 1 and 4 (P < 0.005 and 0.001, respectively) was seen, neither fibrosis stage (χ2 = 3.4882, P > 0.1) nor grade of inflammation (χ2 = 0.0057, P > 0.1) significantly predicted response to treatment. Non‐responders had no or only a limited decline at week 1 and week 4, whereas sustained virological responders had a significant decline at both week 1 and week 4. Area under the (receiver operating characteristic) curve (AUC) revealed that week 12 is better than any other time point in predicting the SVR (AUC = 0.97; 95% CI: 0.94–1.01), (sensitivity 98.3%; 95% CI: 90.7–99.9), (specificity 88.5%; 95% CI: 71.0–96.0), positive predictive value of 94.9% and negative predictive value of 95.8%. A drop of more than 1.17 log viral load at week 1 and viral clearance or decline >3 log were considered as the earliest predictors of SVR. In genotype‐4 patients, while failure to achieve an EVR at week 12 predicts non‐response, an RVR at week1 and week 4 98% guaranteed SVR. These findings further re‐enforce the value of week 12 in the course of IFN treatment. Genotype‐4 patients who show significant viral clearance (>1.17log viral load) by the first week of treatment and viral clearance >3log by week 4 are expected to show SVR and should therefore be assigned to a shorter drug regimen lasting for 24 weeks. Those unfortunate cases who do not achieve viral clearance by week 1 or week 4 should not be deprived from the treatment but rather given more time till week 12 before being classified as non‐responders.

Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment

Summary.  Among individuals with chronic hepatitis C virus (HCV) infection, approximately 30% of patients show persistently normal alanine aminotransferase (PNALT). Individuals with PNALT have been historically excluded from antiviral treatment. However, some studies have reported sudden worsening of disease in patients with PNALT, suggesting the need to treat such individuals. To evaluate this further, we compared fibrosis severity and response to treatment in patients with PNALT to patients with abnormal ALT. In addition, we investigated whether liver histology and schistosomiasis affect response to treatment differently in those with PNALT and abnormal ALT. A retrospective cohort study of 176 HCV‐Genotype 4 (HCV‐G4) patients treated with pegylated interferon (PEG‐IFN) and ribavirin. Of 176 cases studied, 53 (30.1%) had normal ALT. Prevalence of pretreatment severe fibrosis, sustained virological response (SVR) and relapse were not significantly different in patients with PNALT (26%, 66% and 5.7% respectively) compared to those with abnormal ALT (32.5%, 60.7%, and 6.6% respectively). Multivariable logistic regression revealed that pretreatment ALT, pretreatment viral load, inflammation and schistosomiasis were not significantly associated with SVR [OR (95% CI), 0.75 (0.34–1.65); 0.92 (0.61–1.37); 1.64 (0.64–4.18); 0.90 (0.44–1.84) respectively]. Severe fibrosis was the only significant predictor of SVR [OR (95% CI), 0.38 (0.14–0.99)]. PNALT does not reflect the degree of fibrotic changes or predict SVR. Furthermore, schistosomiasis is a predictor of neither fibrosis nor poor response in patients with PNALT. Severe fibrosis is a strong and independent predictor of response to treatment. Therefore, it is important to treat individuals with PNALT levels regardless of schistosomiasis.

Mean Platelet Volume, Red Cell Distribution Width to Platelet Count Ratio, Globulin Platelet Index, and 16 Other Indirect Noninvasive Fibrosis Scores: How Much Do Routine Blood Tests Tell About Liver Fibrosis in Chronic Hepatitis C?

Background and Aim: Many indirect noninvasive scores to predict liver fibrosis are calculated from routine blood investigations. Only limited studies have compared their efficacy head to head. We aimed to compare these scores with liver biopsy fibrosis stages in patients with chronic hepatitis C. Materials and Methods: From blood investigations of 1602 patients with chronic hepatitis C who underwent a liver biopsy before initiation of antiviral treatment, 19 simple noninvasive scores were calculated. The area under the receiver operating characteristic curves and diagnostic accuracy of each of these scores were calculated (with reference to the Scheuer staging) and compared. Results: The mean age of the patients was 41.8±9.6 years (1365 men). The most common genotype was genotype 4 (65.6%). Significant fibrosis, advanced fibrosis, and cirrhosis were seen in 65.1%, 25.6, and 6.6% of patients, respectively. All the scores except the aspartate transaminase (AST) alanine transaminase ratio, Pohl score, mean platelet volume, fibro-alpha, and red cell distribution width to platelet count ratio index showed high predictive accuracy for the stages of fibrosis. King’s score (cutoff, 17.5) showed the highest predictive accuracy for significant and advanced fibrosis. King’s score, Göteborg university cirrhosis index, APRI (the AST/platelet count ratio index), and Fibrosis-4 (FIB-4) had the highest predictive accuracy for cirrhosis, with the APRI (cutoff, 2) and FIB-4 (cutoff, 3.25) showing the highest diagnostic accuracy. We derived the study score 8.5 − 0.2(albumin, g/dL) +0.01(AST, IU/L) −0.02(platelet count, 109/L), which at a cutoff of >4.7 had a predictive accuracy of 0.868 (95% confidence interval, 0.833-0.904) for cirrhosis. Conclusions: King’s score for significant and advanced fibrosis and the APRI or FIB-4 score for cirrhosis could be the best simple indirect noninvasive scores.

Reexamination of the relationship between the prevalence of hepatitis C virus and parenteral antischistosomal therapy among Egyptians resident in Qatar

Egypt has the highest prevalence of recorded hepatitis C virus (HCV) worldwide, estimated nationally at 14.7%, which is attributed to extensive iatrogenic transmission during the era of parenteral antischistosomal therapy (PAT) mass-treatment campaigns. The objective of our study was to attempt to highlight to what extent HCV transmission is ongoing and discuss the possible risk factors. We studied the prevalence of HCV among 7.8% of Egyptians resident in Qatar in relation to age, socioeconomic status, and PAT and discuss the possible risk factors. HCV testing was conducted in 2,335 participants, and results were positive for 13.5%, and 8.5% for those aged below 35 years. The prevalence of HCV in the PAT-positive population was 23.7% (123 of 518, 95% confidence interval [CI] 20.2%–27.6%) compared with 11.2% in the PAT-negative group. Significantly higher HCV prevalence occurred in participants who were older than 50 years (23%, 95% CI 19.3%–27.1%) compared to those aged 45–50 years (19.3%, 95% CI 15.2%–23.8%), 35–45 years (11.1%, 95% CI 8.9%–13.7%), and less than 35 years (8.5%, 95% CI 6.8%–10.4%) (P<0.0001). Insignificant higher prevalence occurred in the low socioeconomic group (14.2%, 95% CI 11.3%–17.4%). Logistic regression analysis revealed that increasing age, history of PAT, bilharziasis, and praziquantel were common risk factors, but there was no relation with dental care. Host genetic predisposition seems to be a plausible underlying factor for susceptibility among Egyptians and intense ongoing infection.

Clinical Application of AIMS65 Scores to Predict Outcomes in Patients with Upper Gastrointestinal Hemorrhage

Background/Aims To evaluate the ability of the recently proposed albumin, international normalized ratio (INR), mental status, systolic blood pressure, age >65 years (AIMS65) score to predict mortality in patients with acute upper gastrointestinal bleeding (UGIB). Methods AIMS65 scores were calculated in 251 consecutive patients presenting with acute UGIB by allotting 1 point each for albumin level <30 g/L, INR >1.5, alteration in mental status, systolic blood pressure ≤90 mm Hg, and age ≥65 years. Risk stratification was done during the initial 12 hours of hospital admission. Results Intensive care unit (ICU) admission, endoscopic therapy, or surgery were required in 51 patients (20.3%), 64 (25.5%), and 12 (4.8%), respectively. The predictive accuracy of AIMS65 scores ≥2 was high for blood transfusion (area under the receiver operator characteristic curve [AUROC], 0.59), ICU admission (AUROC, 0.61), and mortality (AUROC, 0.74). The overall mortality was 10.3% (n=26), and was 3%, 7.8%, 20%, 36%, and 40% for AIMS65 scores of 0, 1, 2, 3, and 4, respectively; these values were significantly higher in those with scores ≥2 (30.9%) than in those with scores <2 (4.5%, p<0.001). Conclusions AIMS65 is a simple, accurate, non-endoscopic risk score that can be applied early (within 12 hours of hospital admission) in patients with acute UGIB. AIMS65 scores ≥2 predict high in-hospital mortality.

Hepatocellular carcinoma in Hepatitis C genotype 4 after viral clearance and in absence of cirrhosis: two case reports

Genotype 4 Hepatitis C virus represents approximately 20% of global Hepatitis C virus infection and is the source of a considerable burden to health-care providers across the globe. Many studies reported that interferon reduces the risk of hepatocellular carcinoma in patients with chronic hepatitis C.Hereby, we are reporting two cases of hepatocellular carcinoma in Hepatitis C virus-genotype 4 after complete viral eradication and in absence of cirrhosis. We aim to highlight the possible direct oncogenic effect of Hepatitis C virus-genotype 4, particularly with concomitant bilharzial infection and the importance of life-log follow up of these patients even in absence of cirrhosis.

Aspartate transaminase to platelet ratio index in hepatitis C virus and Schistosomiasis coinfection

AIM To assess the diagnostic accuracy, of aminotransferase-to-platelet ratio index (APRI) alone and with antischistosomal antibody (Ab) in patients with hepatitis C virus (HCV) and schistosomiasis coinfection. METHODS This retrospective study included medical records of three hundred and eighty three Egyptian men patients who had undergone percutaneous liver biopsy between January 2006 to April 2014 in tertiary care hospital in Qatar for diagnosis or monitoring purpose were selected. Data of patients > 18 years of age were included in the study. The values of HCV RNA titer and antischistosomal antibody titer were also taken into consideration. Patients were excluded from the study if they had any other concomitant chronic liver disease, including; history of previous antiviral or interferon therapy, immunosuppressive, therapy, chronic hepatitis B infection, human immunodeficiency virus co-infection, autoimmune hepatitis, decompensated liver disease, hepatocellular carcinoma, prior liver transplantation, and if no data about the liver biopsy present. RESULTS Median age of patients was 46 years. About 7.1% had no fibrosis, whereas 30.4%, 37.5%, 20.4%, and 4.6% had fibrosis of stage I, II, III, and IV respectively. In bivariate analysis, APRI score, levels of AST, platelet count and age of patient showed statistically significant association with liver fibrosis (P < 0.0001); whereas antischistosomal antibody titer (P = 0.52) and HCV RNA titer (P = 0.79) failed to show a significant association. The respective AUC values for no fibrosis, significant fibrosis, severe fibrosis and cirrhosis of APRI score were 63%, 73.2%, 81.1% and 88.9% respectively. This showed good sensitivity and specificity of APRI alone for grading of liver fibrosis. But the inclusion of anti-Schistosoma antibody did not improve the prediction of fibrosis stage. CONCLUSION The study results suggest that noninvasive biochemical markers like APRI are sensitive and specific in diagnosing the degree of fibrosis and cirrhosis in patients with coinfection of HCV and schistosomiasis as compared to biopsy. The addition of antischistosomal Ab to APRI did not improve sensitivity for predicting the degree of cirrhosis.

High Dose of Lamivudine and Resistance in Patients with Chronic Hepatitis B

Background. Lamivudine is the most affordable drug used for chronic hepatitis B and has a high safety profile. With the daily dose of 100 mg there is progressive appearance of resistance to lamivudine therapy. In our study we used 150 mg of lamivudine daily as a standard dose which warrants further exploration for the efficacy of the drug. Aims of the Study. To assess the efficacy of lamivudine 150 mg daily on resistance in patients with chronic hepatitis B. Methods. This retrospective study consists of 53 patients with chronic hepatitis B treated with 150 mg of lamivudine daily. The biochemical and virological response to the treatment were recorded at a 1-year and 2-, 3-, 4-, and 5-year period and time of emergence of resistance to the treatment was noted. Results. The mean age of the patients was 54 years with 80% being males. The resistance to lamivudine 150 mg daily at 1 year and 2, 3, and 5 years was 12.5%, 22.5%, 37.5%, and 60%, respectively, which is much less compared to the standard dose of 100 mg of lamivudine. Conclusions. Lamivudine is safe and a higher dose of 150 mg daily delays the resistance in patients with chronic hepatitis B.

Platelets as a Possible Reservoir of HCV And Predictor of Response to Treatment

In the era of new Hepatitis C Virus (HCV) therapy, and the detection of extrahepatic HCV reservoirs such as peripheral blood mononuclear cells and platelets, it is important to understand the factors underlying resistance to treatment. Detection and quantitation of HCV-RNA in platelets or leucocytes from patients under antiviral therapy is poorly studied and the limited studies generated contradictory results. Aim: To detect and quantify HCV-RNA in platelets, and to evaluate the relation between HCV-RNA in the serum and the kinetics of HCV-RNA in platelets, in response to treatment. Method: Viral kinetic was tested in 20 chronic HCV genotype4, during the course of therapy. Results: HCV-RNA was detected in sera of all infected patients. The baseline platelet viral load was significantly lower in responders compared to non-responders. Platelet viral load was also related to serum viral load (t=3.39, p=0.001), but not related to platelet count (t=-0.56, p=0.58). ROC curve analysis revealed that in general, platelet viral load at different time points was a better predictor of SVR compared to serum viral load. Conclusion: HCV RNA analysis in whole blood may be more sensitive than platelet-poor plasma, which might underestimate circulating viral load. Early eradication of viremia from platelets is associated with higher rates of SVR. Our data, reconfirm higher HCV-RNA levels in serum compared to platelets. Thrombocytopenia occurring during interferon-based therapy might be a manifestation of viral eradication rather than adverse effects. Our findings warrant testing the sensitivity of platelet viral load as a predictor of poor response.