M. Viganò

Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine†

Progression of hepatitis B in patients with lamivudine‐resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg‐negative patients at the time of phenotypic resistance (group A, >6 log10 copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3‐6 log10 copies/mL of HBV‐DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO‐LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2‐year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV‐related side effects. In conclusion, to optimize antiviral treatment in HBeAg‐negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected. (HEPATOLOGY 2005.)

Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues

BACKGROUND & AIMS In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. METHODS We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.

IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B.

Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)‐induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult‐to‐cure hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg‐negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1‐17) after a median of 23 months (range, 10‐48) of either standard or pegylated (Peg)‐IFN‐alpha therapy. A post‐treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti‐HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post‐treatment follow‐up, 21 patients (21%) cleared serum HBsAg, including 15 who developed >10 IU/mL of anti‐HBs titers. Forty‐eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n = 14) in CC compared to 13% (n = 7) in non‐CC, genotype carriers (P = 0.039). Baseline HBV DNA levels <6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8‐50.6; P = 0.001), ALT levels >136 IU/L (OR, 6.5; 95% CI: 1.8‐22.5; P = 0.003), duration of IFN (OR, 1.16; 95% CI: 1.02‐1.31; P = 0.021), and genotype CC (OR, 3.9; 95% CI: 1.1‐13.2; P = 0.025) independently predicted HBsAg clearance. Conclusions: IL28B polymorphism is an additional predictor of off‐therapy IFN‐related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg‐negative patients chronically infected by genotype D of HBV. (HEPATOLOGY 2013)

Prophylaxis of hepatitis B virus recurrence after liver transplantation in carriers of lamivudine‐resistant mutants

The combination of lamivudine and hepatitis B immunoglobulin (HBIG) reduces the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the efficacy of this strategy and the need for combined therapy with adefovir dipivoxil (ADV) in patients who select lamivudine‐resistant strains (YMDD) before surgery is still unknown. Twenty‐two patients treated with lamivudine (LAM) who underwent LT after YMDD‐mutant selection were studied. In 13 patients, YMDD mutants were associated with an HBV DNA breakthrough greater than 5 log10 (group A: phenotypic resistance), and 11 were treated with ADV to decrease viral load before LT. In the remaining 9 patients who did not experience the viral breakthrough, YMDD mutants were detected only retrospectively in sera stored at the time of LT (group B: genotypic resistance). During 35 months of post‐LT follow‐up, none of the 11 patients of group A treated with ADV before and after surgery (in addition to HBIG and LAM) had HBV recurrence, and neither did any of the 7 subjects of group B treated with LAM before and after transplantation (in addition to HBIG). HBV recurred in 2 patients of group A (untreated with ADV before surgery and transplanted with an HBV DNA exceeding 5 log10) and in 2 subjects of group B (who spontaneously stopped HBIG after surgery). In carriers of YMDD mutants, the risk of post‐LT HBV recurrence is low, provided that preemptive and prophylactic ADV (in addition to LAM and HBIG) treatment is used in highly viremic patients and prophylactic LAM (or ADV) and HBIG therapy is continued in low viremic patients. (Liver Transpl 2005;11:532–538.)

Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B

Objective Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population. Methods 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment. Results Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events. Conclusions In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment. Trial registration number http://ClinicalTrials.gov registration number: NCT01095835.

Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT.

Allogeneic hematopoietic SCT (HSCT) increases the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) carriers but the incidence, risk factors and course of HBV reactivation after HSCT in HBsAg-negative/anti-hepatitis B core antigen (anti-HBc)-positive recipients are not well known. A total of 50 HBsAg-negative/anti-HBc-positive HSCT recipients with onco-hematological diseases, underwent sequential clinical and laboratory examinations, including serum HBsAg, during follow-up. Serum HBV DNA collected at HSCT was retrospectively amplified by a sensitive PCR assay. During 17 months of follow-up, six (12%) patients had seroreverted to HBsAg, 7–32 months after HSCT, with 1- and 5-year cumulative rates of 13 and 22%. HBsAg seroreversion was associated with serum HBeAg higher than 8 log10 copies per ml HBV DNA and a 1.5 to 36 fold increase of serum alanine aminotransferase leading to HBeAg-positive chronic hepatitis B in all patients. Patients with chronic onco-hematological disease and long-lasting immunosuppression following HSCT had a higher risk of HBsAg seroreversion independently of serum HBV DNA levels at HSCT. HBsAg-negative/anti-HBc-positive HSCT recipients with chronic onco-hematological disease carry a significant risk of HBsAg seroreversion and HBeAg-positive chronic hepatitis B, independently of serum levels of HBV DNA at transplantation.

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population

BACKGROUND & AIMS Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. METHODS The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. RESULTS Overall, 28/181 patients followed-up for a median period of 9.6years (range 1-25years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3-94.8) and 62.9% (95% CI, 45.9-75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR=1.00 (95% CI, 0.72-1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43-4.30), for untreated of 3.01 (95% CI, 2.64-3.42) and for decompensated of 6.70 (95% CI, 5.39-8.22). CONCLUSIONS Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.

Dual cut-off transient elastography to assess liver fibrosis in chronic hepatitis B: a cohort study with internal validation.

Aliment Pharmacol Ther 2011; 34: 353–362

Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.

Abstract: Goal: We evaluated the effect of venesections and restricted diet on iron and metabolic indices and liver function tests in patients with insulin‐resistance hepatic iron overload (IR‐HIO).

Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B.

Steatosis is a common histopathological feature of chronic hepatitis B (CHB) and has been associated with severity of liver disease. Recently, the rs738409 I148M patatin‐like phospholipase domain‐containing 3 (PNPLA3) polymorphism has been demonstrated to influence steatosis susceptibility and fibrosis progression in patients with different liver diseases, but no data are yet available for CHB. The aim of this study was to evaluate whether PNPLA3 I148M influences steatosis susceptibility in a large series of patients with CHB. We enrolled 235 treatment‐naïve CHB patients consecutively examined by percutaneous liver biopsy. In ≥2‐cm‐long liver tissue cores, steatosis and fibrosis were staged by Kleiner and METAVIR scores, respectively. The I148M polymorphism was determined by Taqman assays. Steatosis was present in 146 (62%) patients, of whom 24 (10%) had severe (>33% of hepatocytes) steatosis. Steatosis was independently associated with age (odds ratio [OR]: 2.67; confidence interval [CI]: 1.50‐4.92; for age ≥50 years), body mass index (BMI; OR, 2.84; CI, 1.30‐6.76; for BMI ≥27.5 kg/m2), diabetes or impaired fasting glucose (OR, 4.45; CI, 1.10‐30.0), and PNPLA3 148M allele (OR, 1.62; CI, 1.00‐7.00; for each 148M allele). Independent predictors of severe steatosis were BMI (OR, 3.60; CI, 1.39‐9.22; for BMI ≥27.5 kg/m2) and PNPLA3 148M allele (OR, 6.03; CI, 1.23‐5.0; for each 148M allele). PNPLA3 148M alleles were associated with a progressive increase in severe steatosis in patients with acquired cofactors, such severe overweight and a history of alcohol intake (P = 0.005). Conclusion: In CHB patients, the PNPLA3 I148M polymorphism influences susceptibility to steatosis and, in particular, when associated with severe overweight and alcohol intake, severe steatosis. (Hepatology 2013;58:1245–1252)