Khalid I. Bzeizi

Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection

Background: Approximately 20–30% of patients chronically infected with hepatitis C virus (HCV) have persistently normal alanine transaminase (PNALT) levels. These patients are described to have a mild degree of histological liver damage. We aimed to assess the histological liver changes in HCV patients with PNALT.

Safety and efficacy of peginterferon-α2a plus ribavirin treatment in renal transplant recipients with chronic hepatitis C.

BACKGROUND & AIMS Interferon (IFN)-based therapy in chronic hepatitis C virus (HCV)-infected renal transplant (RT) recipients has been associated with a high risk of acute allograft rejection (AAR) and poor efficacy. We assessed the safety and efficacy of PegIFNα-2a and ribavirin (RBV) combination therapy in HCV-infected RT recipients. METHODS Thirty-two adult RT recipients of >12-month duration, infected with HCV genotypes 1 (62.5%) and 4 (37.5%), and significant fibrosis (Metavir ≥ F2) were recruited in an open-label trial with PegIFNα-2a 135-180 μg/week, plus RBV 200-1200 mg/day for 48 weeks, based on the estimated glomerular filtration rate. Safety assessments were performed weekly for 4 weeks, 2-weekly for 8 weeks, and 6-weekly for 36 weeks. Study end points were sustained virologic response (SVR) or development of AAR. Allograft biopsies were performed for 20% increase in creatinine from pretreatment levels, or optionally at week 12 on surveillance protocol. Renal safety was compared with matched untreated historical controls (n=31). RESULTS None of the treated patients showed AAR when biopsied for raised creatinine (12.5%) or during surveillance (37.5%), with incremental and sustained creatinine increases occurring in 6.3% of treated patients and 16.1% of untreated controls (p=0.148), by week 72 assessment. Mean pretreatment and end-of-assessment creatinine in treated patients remained similar (106.8 ± 32.0 vs. 113.4 ± 62.8, respectively; p=0.140), while levels increased significantly in the controls (106.6 ± 35.6 vs. 142.5 ± 93.0, respectively; p=0.013). Rapid, early virologic response (EVR) and SVR occurred in 12.5%, 56.3%, and 37.5% of cases, respectively. SVR was similar in both genotypes (p=1.000). PegIFN and RBV dose reductions were required in 34.4% and 78.1%, respectively; discontinuation was required in 12.5%. Binary logistic regression identified only EVR (OR, 20.4; 95% CI: 2.2-192.6; p=0.008) as an independent predictor of SVR. CONCLUSIONS PegIFN/RBV therapy is not associated with AAR in RT recipients at low risk for rejection but has modest efficacy in the treatment of HCV.

Hepatic granuloma: decreasing trend in a high-incidence area

Background: Hepatic granuloma (HG) has a high reported incidence in Saudi Arabia (14.6%). We aimed to identify the incidence of HG in our centres and review its presenting features and underlying aetiology.

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B

Summary.  Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut‐off 20 000 vs 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088–0.868; P = 0.0276) and milder (A0–1) necroinflammatory grade (OR, 0.135; CI: 0.063–0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20 000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51%vs 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg‐negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut‐offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.

Efficacy and Safety of Simeprevir or Daclatasvir in Combination With Sofosbuvir for the Treatment of Hepatitis C Genotype 4 Infection

Introduction: The combination of sofosbuvir (SOF) with simeprevir (SMV) or daclatasvir (DCV) is very effective in treating hepatitis C virus (HCV) infection, particularly genotype (GT) 1. However, the data on GT4 are very limited. We aimed to determine the efficacy and safety of SOF in combination with either SMV or DCV in GT4-infected patients. Patients and Methods: In this real life, prospective, observational study, HCV (GT4) patients (n=96) were evaluated in 2 groups on the basis of the 12-week treatment regimen they received. Group 1 (n=56) patients were treated with SOF and SMV±ribavirin (RBV), whereas group 2 patients were treated with SOF and DCV±RBV (n=40). The primary efficacy endpoint was sustained virologic response 12, whereas the primary safety endpoint was drug discontinuation or occurrence of grade 3/4 adverse events. Results: The mean age was 49±14.6 years (59.4% men). Cirrhosis was present in 53.6% and 35.0% of groups 1 and 2, respectively, whereas 27 patients (48.2%) in group 1 and 21 patients (52.5%) in group 2 had failed prior interferon-based treatment. The median pretreatment HCV-RNA log10 was 6.1 (3.6 to 7.0) and 6.0 (3.6 to 7.2) IU/mL in groups 1 and 2, respectively. RBV was given to 17 patients (30.4%) in group 1 and 2 patients (5%) in group 2. All patients achieved sustained virologic response 12 (100%). Adverse events occurred in 32% of patients (grade 1 and 2), but none discontinued treatment. One patient died in the SMV group (not related to treatment). Conclusions: SMV/SOF or DCV/SOF combinations are safe and highly effective in HCV-GT4 treatment. Cirrhosis and failure of prior interferon-based treatment did not influence treatment response.

Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C.

Background and aim: Histological changes in hepatitis C virus (HCV)‐infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; ≤19/30U/L for females/males). We assessed significant fibrosis (≥F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT).

Coincidence of acute Brucella hepatitis and dengue fever or serologic cross-reactivity?

Hepatic involvement in brucellosis is not uncommon since 10-20% of patient infected with brucella species can have abnormal liver function tests. The usual presentation of brucella hepatitis is in the form of chronic granulomatous hepatitis with mild to moderate elevation of liver enzymes, while acute hepatitis is rare. We report a young patient who presented with acute brucella-induced hepatitis and co-infection with dengue hemorrhagic virus resulting in severe elevation of liver enzymes and absence of granuloma on histology. His mother also simultaneously tested positive for both infections. The patient responded well to anti-brucella therapy with normalization of his liver profile. We discuss, herein, the hepatic involvement of these two infections and discuss the possible serological cross-reactivity between brucella and dengue fever virus.

Predictors of significant fibrosis in chronic hepatitis B patients with low viremia.

Background and Aim: The data on the prevalence and predictors of significant fibrosis (≥F2, METAVIR) in chronic hepatitis B virus (HBV) patients with low viremia are limited. We aimed to assess both the prevalence predictors of ≥F2 fibrosis in hepatitis B envelope antigen-negative patients with HBV DNA <20,000 IU/mL. Methods: Hepatitis B envelope antigen-negative patients (n=213) with mean HBV DNA <2000 IU/mL (n=97) and HBV DNA 2000 to 20,000 IU/mL (n=116) were included and all had liver biopsy. Variables significantly associated with ≥F2 fibrosis on an univariate analysis were included in a multivariate logistic regression model. Results: Overall, 40 (18.8%) patients had ≥F2 fibrosis, with no difference between those with mean HBV DNA <2000 IU/mL (19.6%) compared with patients with HBV DNA of 2000 to 20,000 IU/mL (18.1%; P=0.782). Fibrosis ≥F2 was similar in patients with HBV DNA <2000 versus 2000 to 20,000 IU/mL in relation to varying alanine aminotransferase thresholds (P>0.05), and was less frequent in persistently normal alanine aminotransferase patients (13.6%) when compared with those with elevated or fluctuating levels (25.3%, P=0.030). Fewer patients under 40 years of age had ≥F2 fibrosis (12.5%) as compared with older ones (28.2%; P=0.004). Logistic regression analysis identified higher aspartate aminotransferase [odds ratio (OR), 6.21; 95% confidence interval (CI), 2.48-15.54; P<0.0001], lower albumin (OR, 0.86; 95% CI, 0.78-0.95; P=0.002), platelet count (OR, 0.99; 95% CI, 0.98-0.99; P=0.013), and age (OR, 1.05; 95% CI, 1.01-1.09; P=0.024) as independent predictors of significant fibrosis. Conclusions: A small but significant minority of HBV patients with low viremia harbor significant fibrosis, although its rate is not different in those with viremia above or below 2000 IU/mL. Our findings may guide in decisions regarding liver biopsy and treatment in this category of patients.

Hepatitis C treatment: trial by design.

Hepatitis C is a major health problem in Saudi Arabia and, as is the case, in most parts of the world. The standard treatment of all genotypes of hepatitis C consists of pegylated interferon (IFN) alfa and ribavirin combination therapy. Majority of hepatitis C viruses (HCV) patients in the Gulf region and the Middle East in general are infected with Genotype 4. Genotype 4 can be singled out as the one least studied among all the other genotypes. This is not entirely surprising considering that research is not a priority, to put it mildly, in the Middle-East. In this issue of the Saudi Journal of Gastroenterology, Al Ashgar and colleagues report the treatment outcome of 335 HCV patients treated with peginterferon α-2a and ribavirin combination therapy.[1] The study is retrospective; however, it was well conducted and covered the essentials expected in a well-designed study. The protocol of management was well defined and the patients were managed and monitored closely according to the standardized protocol. The study is designed to assess the efficacy and safety of 48 weeks peginterferon α-2a and ribavirin combination therapy. The authors also looked at the predictors of sustained virologic response (SVR) in their cohort of 335 consecutive Saudi patients with HCV infection treated in their center. Eighty seven percent of patients completed treatment and about 55% achieved SVR. On intention-to-treat analysis, the overall number of patients with SVR was about 48%. The divergence of the studys findings from the prospective studies published earlier for genotype 4 lies mainly in the overall SVR.[2,3] The authors of the study have indicated that the reason for lower SVR than other gentotype 4 studies is the fact that they have included patients with co-morbidities, non-responders to previous IFN treatment organ transplant patients, and those with co-infection with HBV or HIV infections. It is difficult to ascertain how much the design of the study could have impacted on the relatively low SVR. As with any retrospective and post-marketing study, the level of motivation and compliance of patients is known to be relatively lower than in patients recruited for prospective studies. A more plausible explanation for the low SVR could be the difference of genotype 4 subtypes. The largest number of studies in genotype 4 infected patients came from Egypt where the SVR was generally higher than the findings of this study. Genotype 4a is the most common in Egypt unlike Saudi Arabia where genotypes 4c/4d are the most prevalent as found by an epidemiological study by Shobokshi et al.[4] Roulot et al.[5] analyzed epidemiological features and SVR rates in a retrospective study of 1532 HCV-4-infected patients, including 1056 patients infected in France, 227 immigrants infected in Egypt, and 249 in sub-Saharan Africa. The 4a subtype was largely predominant (93%) among patients infected in Egypt. SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3%, and 32.4%, respectively; P < 0.05). An overall better response was observed in patients infected with the 4a subtype compared with 4d subtype-infected individuals. Patients in the French group infected with the 4a subtype showed SVR rates similar to those of patients in the Egyptian group. Another interesting finding of the study worth mentioning here is the SVR (34.6%) of patients who previously received conventional IFN therapy. SVR was better than the results of many studies in both genotype 1 and genotype 4 and the authors attributed this to a potential immunological mechanisms.[6,7] The degree of fibrosis as well as viral load did not appear to be predictive of response to treatment, findings that again differ from what has been established from other studies particularly the prospective ones. The time lag from taking the biopsies and the initiation of treatments was listed as one of the explanation for lack of difference in SVR according to the degree of fibrosis. It remains, however, difficult to come with plausible explanations for such divergence from the findings of other studies except perhaps for the fact that this study is a retrospective one. Nevertheless, the study is an important addition in this region towards the management of HCV patients. The fact remains that the overall SVR particularly for genotypes 1 and 4 is sub-optimal as this study and similar ones have shown. Taking a lead from this study, there is a need for optimizing the use of existing agents and tailoring the treatment to the individual patients in order to maximize the SVR. The peginterferon-based treatment for HCVwill be with us for the foreseeable future and therefore, randomized multicenter trials, particularly for HCV genotype 4, are still needed utilizing this treatment modality. Clinical trials should aim to study aspects such as treatment duration, optimum ribavirin dosing, and utility of RVR. Likewise, every effort should be made every effort should be made to explore the place of the newer class of agents, the small molecules that are viral enzyme inhibitors in treatment of genotype 4 patients. The protease enzyme inhibitors appeared to be the most promising in recent phase II/III trials for genotype 1. Such studies should be extended to include genotype 4 patients who are equally difficult to treat. The resources available in this region certainly match the huge scale of disease burden and those of us ideally positioned should take the lead in setting up relevant clinical trials as early as possible.

Clinical Presentation, Treatment Outcome and Predictors of Severity in Autoimmune Hepatitis: A Retrospective, Multicenter Experience: Aljumah AA et al . Predictors of severity in AIH

AIM: Autoimmune Hepatitis (AIH) is a chronic hepatitis of unknown etiology. It affects adults and children and can progress to cirrhosis. We aim to investigate the mode of presentation, predictors of severity and treatment outcome of AIH in Saudi patients. METHODS: This is a multicenter retrospective study that involved patients diagnosed with AIH from 3 tertiary hospitals. Clinical, biochemical, radiological and histopathological data were collected and treatment outcomes were reported. RESULTS: A total of 212 patients were included. Female: male ratio was 3:2 and the mean age was 36.2 ± 16.8 years while 50 patients (23.6%) were above age of 50. Abnormal liver function tests (LFTs) were found in (45%). Presentation was chronic in 37.7%, acute in 30.7%, with evidence of liver cirrhosis in 28.8% and with a fulminant disease in 2.8%. Antinuclear antibody (ANA) and Anti-smooth muscle antibody (ASMA) were negative in 65 (30.6%) and 74 (35%) patients respectively. Pre-treatment liver biopsies in 166 patients showed advanced fibrosis (stage 3 and 4) in 63.3%. On multivariate analysis, platelets, alanine transaminase (ALT) level and immunoglobulin G (IgG) level were predictors of fibrosis. Complete response was achieved in 74.5% while 9% had partial response and 16.5% had no response to treatment. CONCLUSION: The majority of AIH patients had advanced fibrosis at the time of diagnosis and liver cirrhosis was found in nearly one-third of cases. IgG, ALT, and platelet were predictors of advanced fibrosis. Complete response to treatment was achieved in two-third of patients. Relying on autoimmune markers for diagnosis can be misleading.