Characterization of antiviral resistance mutations among the Eastern Indian Hepatitis B virus infected population.

BACKGROUND: Antiviral therapy using nucleos(t)ide analogues (NAs) is an effective control measure of chronic hepatitis B virus (HBV) infection; however they need long term treatment. Presence of drug-resistance mutations may get in the way of the efficacy of antiviral therapy. Our study was aimed at defining the prevalence of HBV drug-resistance in HBVrt region in a population of 147 HBsAg positive patients. FINDINGS: HBV/D has shown multiple types of HBVrt mutations both among treatment naïve (65.0%, 13 of 20 HBV/D) and treated patients (56.2%, 9 of 16 HBV/D). In additional, several mutations, with a suggested role in drug resistance, were detected among the treatment naïve as well as the treated patients. The mutations reported to be involved in reduction of drug effectiveness, was common among non-responders to therapy as well as among the naïve patients. Notably, classical antiviral resistance mutations (rtL80I/V-rtI169T-rtV173L-rtL180M-rtA181T/V/S-rtT184A/S/G/C-rtA194T-rtS202C /G/I -rtM204V/I-rtN236T-rtM250V) were not detected. CONCLUSION: The prevalence of putative NAr mutations among non responders to therapy suggests that they might have role in reduced efficacy of currently available antivirals and requires further investigations.

Variations in the functional domain of basal core promoter of hepatitis B virus among Eastern Indian patients with prevalence of genotypes A, C, and D among the same ethnic population.

Mutations in the basal core promoter (BCP) and precore (PC) regions are associated with persistent and intermittently high hepatitis B virus (HBV) replication in several patients. The variability in the functional domains of BCP and PC region of HBV and their association with disease progression and clinical outcome were assessed in Eastern India, an unique region where three HBV genotypes, A, D, and C are prevalent among the same ethnic group. PCR amplification and direct sequencing of BCP and PC region was done on sera obtained from 130 HBsAg positive subjects with different clinical presentations. Associations of the apparent risk factors with clinical advancement were evaluated by statistical methods including multiple logistic regression analyses (MLR). HBV genotype A was present in 33.08%, C in 25.38%, and D in 41.54% cases. Genotypes A and C were associated with higher rate of T1762/A1764 mutations than the most predominant genotype D. HBeAg negative state was associated with considerably higher rate of C1753 mutation. T1762/A1764 along with C1753 was common among cirrhosis and T1762/A1764 without C1753 was frequent among chronic liver disease cases. No significant association was found between A1896 point mutation and clinical status. Multivariate analysis revealed that T1762/A1764 double mutation, HBV/A, age ≥25 years, C1753 and A1899 were critical factors for clinical advancement while age ≥25 years and C1753 as significant predictor for cirrhosis in comparison with chronic liver disease. In conclusion, the analysis of the BCP variability may help in monitoring the progression towards advanced liver disease in Eastern Indian patients.

Differential pattern of pre-S mutations/deletions and its association with hepatitis B virus genotypes in Eastern India.

The presence of three different HBV genotypes (A, C and D) in Eastern India provided us a unique opportunity to study HBV pre-S mutants in these genotypes and subtypes among the same ethnic population. Furthermore, we also aimed to investigate the association of the HBV pre-S mutation with clinical outcome. Pre-S1-S2 and S gene was amplified and sequenced from 86 HBsAg positive study subjects with varying clinical manifestation. The genetic variability in the pre-S region (mutations) was studied with respect to different HBV genotypes, subtypes and different clinical categories. Six different types of HBV pre-S mutations were detected in 25 cases (29.07%), among which pre-S2 start codon mutation (28.0%) and pre-S2 deletion (24.0%) were most common. Pre-S mutation was highest in HBV/C (7/18; 38.89%) followed by HBV/A (9/27; 33.33%) and HBV/D (9/40; 22.50%). Pre-S1 deletion is common in HBV/D, whereas pre-S2 start codon mutation and pre-S2 deletions are frequent among HBV/A and HBV/C, respectively. Interestingly, in HBV/A and HBV/C the tendency of mutation/deletion increases from pre-S1 to pre-S2 region while in HBV/D the opposite tendency was observed. A significantly higher association of pre-S mutation (p=0.013) and pre-S2 deletion/ablation (p=0.016) was found among the HBeAg negative cases. Pre-S1 deletion and pre-S2 deletion were common among the ASC and CLD cases respectively, while pre-S2 start codon mutation was significantly associated with cirrhosis (p<0.05). The study underscores the association of types of pre-S mutations with particular HBV genotype and clinical outcome in the study population.

Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial.

AIM: To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and to evaluate the role of different liver function scores in predicting prognosis. METHODS: Sixty-eight patients with severe alcoholic hepatitis (Maddrey score > or = 32) received pentoxifylline (n = 34, group I) or prednisolone (n = 34, group II) for 28 d in a randomized double-blind controlled study, and subsequently in an open study (with a tapering dose of prednisolone) for a total of 3 mo, and were followed up over a period of 12 mo. RESULTS: Twelve patients in group II died at the end of 3 mo in contrast to five patients in group I. The probability of dying at the end of 3 mo was higher in group II as compared to group I (35.29% vs 14.71%, P = 0.04; log rank test). Six patients in group II developed hepatorenal syndrome as compared to none in group I. Pentoxifylline was associated with a significantly lower model for end-stage liver disease (MELD) score at the end of 28 d of therapy (15.53 +/- 3.63 vs 17.78 +/- 4.56, P = 0.04). Higher baseline Maddrey score was associated with increased mortality. CONCLUSION: Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis.