Search

Direct‐acting agents (DAAs) have launched a new era of hepatitis C virus (HCV) treatment. As aged individuals comprise a large percentage of HCV‐infected patients, the effectiveness and safety of DAAs in the elderly have come under scrutiny. This meta‐analysis aimed to evaluate the efficacy and safety of DAAs in elderly patients. After a systematic search in PubMed (MEDLINE), Embase, OVID MEDLINE, the Cochrane Library and other databases, two investigators reviewed relevant abstracts and selected manuscripts for examination. The sustained virologic response (SVR) and adverse event (AE) rates were calculated with a random‐effects model. Ninety studies evaluating SVR rates of elderly patients (≥65 years old) receiving DAAs were selected. DAAs in elderly patients exhibited a notable SVR rate of 96% (95% confidence interval [CI]: 95%–97%), accompanied by comparable rates in subgroup analyses. The comparison of SVR rates in elderly and non‐elderly patients indicated no significant discrepancy (odds ratio [OR] 1.01, 95% CI: 1.00–1.01). The overall event rate of AEs was 45% (95% CI: 31%–60%), though AE rates varied by subgroups. Furthermore, AEs were comparatively more frequent (OR 1.15, 95% CI: 1.04–1.28) in the elderly than non‐elderly, especially in subgroups such as SAE (OR 1.89, 95% CI: 1.52–2.36) and dose reduction in ribavirin (OR 1.90, 95% CI: 1.53–2.36). However, in the ribavirin (RBV)‐free regimen, there was no significant difference in the incidence of AEs between the elderly and non‐elderly groups. DAAs have high efficacy in elderly patients. Considering the possibility of AE, the RBV‐free regimen should be given prior consideration for the treatment of elderly patients with HCV. [ABSTRACT FROM AUTHOR]

As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real‐world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real‐world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan. Patients were observed for safety outcomes during and 4 weeks after treatment, and for sustained virologic response at 12‐weeks post‐treatment (SVR12). Incidence rates (IRs) of adverse drug reactions (ADRs) and serious ADRs (SADRs) and SVR12 rates were assessed overall and by subgroups. ADR and SADR IRs were low (2.26 and 0.17 per 100 person‐months, respectively) and did not significantly differ in elderly patients or those with presence of compensated cirrhosis, worsening fibrosis or HCC. SVR12 rates were high overall (98.5%) and across subgroups investigated (≥94%), including patients who were elderly (98.2%), treatment‐experienced (97.6%), advanced fibrotic (≥95.8%), had existing NS5A resistance‐associated substitutions reported pre‐treatment (95.0%), compensated cirrhosis (95.7%), HCC (94.0%) and other chronic liver diseases (96.1%). In this large, real‐world observational study of Japanese patients with HCV GT1 infection, LDV/SOF treatment resulted in low incidence of adverse events, with high real‐world effectiveness, even among patients with potentially higher risks of adverse safety outcomes and treatment failure. [ABSTRACT FROM AUTHOR]

The advent of highly effective and well‐tolerated direct antiviral antivirals (DAAs) has dramatically changed the landscape of chronic hepatitis C. The effect of DAAs in older adults is difficult to determine since patients aged ≥ 65 years were too few in most clinical trials and data mainly come from observational studies. We performed a systematic review and meta‐analysis to evaluate the efficacy and safety of DAAs in patients aged 65 and older. PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, HCV‐Trials.com databases were searched for literature published until 1 December 2017. English language articles reporting results of phase 2 or 3 randomized controlled trials (RCTs), single‐arm clinical trials (SATs) and observational studies were included in the final analysis. All studies included subgroups of older patients and compared their outcomes with younger individuals. By using a random‐effects or fixed‐effects model, odds ratio (OR) was calculated for the efficacy and safety. Heterogeneity was tested using I2 statistics. Thirty‐seven studies reported data on the DAA efficacy. The OR was 1.66 (95%CI: 1.00‐2.75; P = 0.06) in meta‐analysis of RCTs, and similar results were found in SATs and observational studies. HCV genotype, stage of fibrosis or HIV co‐infection did not affect the rate of SVR in older persons. Prevalence of anaemia (OR 0.26 95%CI: 0.09‐0.69; P = 0.007) (OR 0.25 95%CI: 0.09‐0.69; P = 0.007) and skin complaints (OR 0.61 95%CI: 0.45‐0.83; P = 0.001) was higher in older adults. Finally, geriatric patients affected by chronic HCV infection can be safely treated with DAAs with the same efficacy reported in younger adults. [ABSTRACT FROM AUTHOR]

Summary: Although HCV infection is highly prevalent in East Asia, these patients have been underrepresented in HRQL studies. Here, we assess HRQL in East Asian HCV patients treated with different anti‐HCV regimens. Patients completed Short Form‐36 (SF‐36) before, during and after treatment. A total of 989 HCV patients were enrolled in two phase 3 clinical trials [China: 60.2%, South Korea: 22.4%, Taiwan: 17.4%; genotype 1: 55.3%, treatment‐naïve: 57.5%; cirrhosis: 14.0%]. Patients received pegylated interferon, sofosbuvir and ribavirin (Peg‐IFN + SOF + RBV; n = 130, genotypes 1, 6) or SOF + RBV (n = 475, all genotypes) or SOF and ledipasvir (LDV/SOF; n = 384, genotype 1). The SVR‐12 rates were 94.6%, 96.2% and 99.2%, respectively (P = 0.005). During treatment, Peg‐IFN + SOF + RBV‐treated group experienced significant declines in most HRQL scores (by the end of treatment, mean decline up to −12.0 points, all P < 0.05). Patients on SOF + RBV had milder HRQL impairment (up to −5.8 points, P < 0.05 for 5 of 8 HRQL domains). In contrast, patients receiving IFN‐ and RBV‐free regimen with LDV/SOF had their HRQL scores improve (mean up to +4.3 points, P < 0.0001 for 3 of 8 scales). In multivariate analysis, receiving Peg‐IFN + SOF + RBV was consistently independently associated with HRQL impairment during treatment (β: −10.3 to −16.4) and after achieving SVR‐12 (β: −4.4 to −9.1) (all P < 0.01). The results were reproduced in a subgroup of patients enrolled in China. We conclude that in East Asian patients with HCV, HRQL improved from baseline after treatment with LDV/SOF but not with Peg‐IFN + RBV‐containing or Peg‐IFN‐free RBV‐containing regimens. The HRQL impairment associated with the use of Peg‐IFN persists even after achieving sustained virologic clearance. [ABSTRACT FROM AUTHOR]

Summary: Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision‐analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10 000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state‐transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all‐oral direct‐acting anti‐virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan‐specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality‐adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness‐to‐pay threshold of ¥4‐to‐¥6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves ¥850 446.73 and ¥338 229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment‐related QALY improvements were ¥10 576 000, ¥13 220 000 and ¥15 864 000 ppt (willingness‐to‐pay thresholds of ¥4 million, ¥5 million and ¥6 million). Total economic savings of treatment with DAAs (vs no treatment) was ¥7 526 372.63, ¥10 170 372.63 and ¥12 814 372.63, at these different willingness‐to‐pay thresholds. In conclusion treatment of HCV GT1b with all‐oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC. [ABSTRACT FROM AUTHOR]

Summary: Fulminant hepatic failure is a life‐threatening disease. Hepatitis A virus (HAV) can cause fulminant hepatic failure and death in about 0.2% of cases. Extensive destruction of infected hepatocytes by immune‐mediated lysis is thought to be the cause. We aimed to evaluate the use of steroid therapy in children with fulminant HAV. This study included 33 children with fulminant HAV in two groups. Steroid group: comprised of 18 children who received prednisolone (1 mg/kg/d) or its equivalent dose of methylprednisolone, and the nonsteroid group: comprised another 15 children who did not receive steroid therapy. Age and sex were matched for both groups (P > .05), and they were comparable regarding baseline clinical and laboratory characteristics. Of the steroid group, 15 patients survived and 3 died, while in the nonsteroid group, 4 patients survived and 11 died (P = .001). Of the living patients, 15 of 19 (78.9%) received steroids while only 3 of 14 (21.4%) of the dead patients received steroids (P = .001). Stepwise regression analysis showed that steroid therapy was the only independent variable associated with recovery (P = .001). Steroid therapy in children with fulminant HAV associated significantly with improved outcome and survival. Future studies on a larger population size are strongly recommended. [ABSTRACT FROM AUTHOR]

Summary: It is unclear whether multiple nonstructural (NS) 5A resistance‐associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor‐naïve patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor‐naïve patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy. [ABSTRACT FROM AUTHOR]

Chronic, untreated hepatitis C virus (HCV) infection is associated with a poor clinical prognosis and a detrimental impact on patients' lives, including on work productivity. To estimate the value of productivity losses due to genotype 1 (GT1) HCV infection in Hong Kong, Singapore, South Korea and Taiwan and to estimate the potential productivity gains associated with treating patients with ledipasvir/sofosbuvir (LDV/SOF) therapy, an economic model was developed with a time horizon of 1 year. Hepatitis C virus patients entered the model at 12 weeks post- treatment, having achieved or not achieved sustained virological response (SVR). Absenteeism and presenteeism rates were taken from a pooled analysis of data from the ION 1-3 studies. These rates were converted into hours of lost productivity, multiplied by the average wage and applied to the total employed, adult GT1 population in each country. Results were compared assuming no treatment, and assuming all patients were treated with LDV/SOF. Total productivity losses due to untreated HCV were: $11.3 million, $17.1 m, $146.0 m and $349.1 m in Hong Kong, Singapore, South Korea and Taiwan. LDV/SOF treatment resulted in economic gains of $4.5 m, $6.8 m, $58.7 m and $138 m, respectively. These gains were due to reduced presenteeism. The results were sensitive to changes in the prevalence of HCV and the average wage. In conclusion, productivity losses due to untreated HCV infection represent a substantial economic burden. By instituting universal HCV treatment with LDV/SOF (or other therapies with high SVR rates), productivity gains can be achieved. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus ( HCV) and HBV co-infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti- HCV therapy and compared those between interferon ( IFN)-free direct-acting antiviral ( DAA) therapies and IFN-based therapies. Three hundred and twenty-two patients with HCV infection receiving anti- HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV- DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti- HBs positivity, changes in anti- HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN-free DAA therapies and 72 were treated with IFN-based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN-free DAA therapies, while no patient developed HBV reactivation after IFN-based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti- HBs titre to <12 mIU mL−1 by the end of treatment. The decline changes of anti- HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8 weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN-free DAA therapies. Low levels of anti- HBs and their decrease to <12 mIU mL−1 after treatment are significant risk factors for HBV reactivation or reappearance. [ABSTRACT FROM AUTHOR]

This open-label, clinical experience investigated the safety and efficacy of direct-acting antiviral ( DAA) hepatitis C virus ( HCV) therapy in Myanmar; 344 patients completed treatment between June 2015 and May 2016. Patients with HCV genotypes 1-4 and 6 received one of four treatments: (i) Peg-interferon ( PEG- IFN)+sofosbuvir ( SOF)+ribavirin ( RBV) for 12 weeks, (ii) SOF+ RBV for 24 weeks, (iii) ledipasvir ( LDV)+ SOF for 12 weeks or (iv) daclatasvir ( DCV)+ SOF+ RBV for 12 or 24 weeks. Genotype 3 was most common (n=133, 38.7%), followed by genotype 6 (n=122, 35.5%) and genotype 1 (n=86, 25%). Overall, 91% of patients achieved sustained virologic response ( SVR); 99% in group 1, (n=148/149), 90% in group 2 (n=95/106), 78% in group 3 (n=65/83) and 100% in group 4 (n=6/6). In group 3, SVR rates were 96.8% in genotype 1 (n=30/31) and 64.1% in genotype 6 (n=25/39). Multivariable regression analysis identified advanced fibrosis (F3-4) ( OR=.16 CI: 0.05-0.57, P=.005), genotype 6 ( OR=.35, CI: 0.16-0.79, P=.012) and diabetes ( OR=.29, CI: 0.12-0.71, P=.007) as negative independent predictors of response. Adverse events were mild with all-oral therapy. Conclusion: DAA therapy ± PEG- IFN achieved high SVR rates. Genotype 6 patients had a low SVR to 12 weeks of LDV and SOF raising the need for other regimens, RBV or longer treatment duration in this population. [ABSTRACT FROM AUTHOR]

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV- NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response ( SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance. [ABSTRACT FROM AUTHOR]

Legalon SIL ( SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle ( Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus ( HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA- SCID-chimeric mice with humanized livers. Chronically HCV-infected mice ( n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin ( hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated ( r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes. [ABSTRACT FROM AUTHOR]

Clevudine has been approved for the treatment of chronic hepatitis B (CHB) in South Korea. However, its long-term antiviral effect and safety awaits more study. The aim of this study was to evaluate antiviral efficacy, predictors of virologic response, and development of myopathy after clevudine therapy for CHB. The study included 102 nucleoside naïve CHB patients who had received clevudine for more than 6 months with good compliance. The median duration of clevudine treatment was 53 weeks (range, 25-90 weeks). A retrospective analysis of data retrieved from medical records was performed. The cumulative rate of virologic response [hepatitis B virus (HBV) DNA level <2000 copies/mL] at 48 weeks of clevudine therapy was 81%, and cumulative rate of clevudine resistance was 11% at 60 weeks of treatment. Independent predictors of virologic response to clevudine therapy were hepatitis B e antigen (HBeAg) negativity and rapid decrease of viral load during the early phase of treatment. The clevudine-related myopathy developed in 3.9% of patients, and was reversible after discontinuation of clevudine. Clevudine showed a potent antiviral response, and its effect was higher in HBeAg-negative patients, with rapid viral load reduction after therapy. However, long-term therapy for more than 1 year resulted in the development of considerable resistance and myopathy. Therefore, we should consider alternative antiviral agents if clevudine resistance or clevudine-induced myopathy is developed in patients on clevudine for the treatment of CHB. [ABSTRACT FROM AUTHOR]

Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8–4.8 P value <0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6–89.3), significantly better than the clearance rates in untreated patients ( P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated. [ABSTRACT FROM AUTHOR]

A large number of studies have reported on spontaneous viral clearance rates in acute hepatitis C infection, however most have been small, and reported rates have varied quite widely. To improve the precision of the estimated rate of spontaneous viral clearance, a systematic review was conducted of longitudinal studies. Factors associated with viral clearance were also examined. Inclusion criteria for studies were: longitudinal assessment from time of acute hepatitis C; hepatitis C virus RNA analysis as determinant of viral clearance; untreated for acute hepatitis C. Information on study population, and factors that may influence viral clearance were extracted from each study. Viral clearance was defined among individuals with at least 6 months follow-up following acute hepatitis C. The number of subjects with viral clearance was expressed as a proportion for each study and a weighted mean for proportion was calculated. A total of 31 studies were examined. Study populations included nine studies of post-transfusion hepatitis, 19 of acute clinical hepatitis, and three of sero-incident cases. In total, data was available for 675 subjects and the mean study population was 22 (range 4–67). The proportion with viral clearance ranged from 0.0 to 0.8, with a weighted mean of 0.26 (95% CI 0.22–0.29). Factors associated with viral clearance were female gender and acute clinical hepatitis C study population. Further studies are required to more clearly define predictors of clearance and guide therapeutic intervention strategies. [ABSTRACT FROM AUTHOR]

Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also be responsible for differences in the clinical outcome and response to antiviral treatment in different population groups. [ABSTRACT FROM AUTHOR]

The biological implications of substitutions L60V and I97L in the core (c) gene of hepatitis B virus (HBV) were investigated in order to determine whether they could change the immunogenicity of HBcAg or influence the immune response in mice. Three strains of recombinant adenoviruses– AdHBV-WT, AdHBV-L60V and AdHBV-I97L– containing wild-type or mutant HBV genomes were constructed using the AdEasy system and used to infect BALB/c mice intranasally. Infected mice produced anti-HBc efficiently to comparable levels. IgG1 and IgG2a specific for HBcAg were present in mice sera, and the response was dominated by IgG2a. The lymphocyte proliferative response specific for HBcAg was assessed by [3H]-thymidine uptake. We found that AdHBV-WT induced a stronger T-cell proliferation response than AdHBV-L60V and AdHBV-I97L. In conclusion, the L60V and I97L substitutions had no influence on humoral immune responses, but could downregulate T-cell responses to HBcAg, suggesting that L60V and I97L were immune escape mutants. [ABSTRACT FROM AUTHOR]

There are eight genotypes and nine subtypes of HBV. Small differences in geographical origin are associated with sequence changes in the surface gene. Here, we compared core gene sequences from different genotypes and geographical regions. Specific combinations of 24 amino acid substitutions at nine residues allowed allocation of a sequence to a subtype. Six of these nine residues were located in different T cell epitopes depending on HBV geographical area and/or genotype. Thirty-seven nucleotide changes were associated uniquely with specific genotypes and subtypes. Unique amino acid and nucleotide variants were found in a majority of sequences from specific countries as well as within subtype ayw2 and adr. Specific nucleotide motifs were defined for Korean, Indian, Chinese, Italian and Pacific region isolates. Finally, we observed amino acid motifs that were common to either South-east Asian or Western populations, irrespective of subtype. We believe that HBV strains spread within constrained ethnic groups, result in selection pressures that define sequence variability within each subtype. It suggests that particular T cell epitopes are specific for geographical regions, and thus ethnic groups; this may affect the design of immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

Re-treatment with interferon-α alone for chronic hepatitis C nonresponders to interferon-α monotherapy is almost ineffective. This multicentre, randomized, parallel-group, dose-finding study evaluated the efficacy of interferon-β-1a in the treatment of chronic hepatitis C patients unresponsive to interferon-α. A total of 267 patients were randomized to one of four groups: subcutaneous interferon-β-1a 12 MIU (44 μg) or 24 MIU (88 μg) administered three times weekly or daily. Patients were treated for 48 weeks and then followed up for an additional 24 weeks. There was a trend towards a dose–response relationship regarding virological [loss of detectable serum hepatitis C virus (HCV) RNA] and biochemical response (normalization of serum alanine aminotransferase). Overall, 22 patients (8.3%) had a virological response at the end of treatment; nine patients (3.4%) had a sustained virological response (SVR). Strikingly, 21.7% (5/23) of Chinese patients achieved SVR. Univariate analysis revealed that race was the only variable related to SVR [odds ratio (OR) 16.6; 95% CI 4.1–67.3;P < 0.0001]. Multiple logistic regression analysis also confirmed that more Chinese patients achieved SVR than non-Chinese patients (OR 12.3; 95% CI 2.6–59.3;P = 0.0017). In addition, complete clearance of HCV-RNA occurred earlier in Chinese than in non-Chinese responders (median 2vs30 weeks;P = 0.020). Thirty-six patients were withdrawn from treatment because of adverse events. Most adverse events were mild or moderate in severity. In conclusion, interferon-β-1a provided considerable clinical benefit in Chinese patients with chronic hepatitis C unresponsive to interferon-α. The evaluation of interferon-β-1a in this setting is progressing. [ABSTRACT FROM AUTHOR]

Hepatitis B is a serious disease that is endemic in many parts of the world. A significant proportion of patients with chronic hepatitis B (CHB) are infected with a variant form of the hepatitis B virus (HBV) which decreases or abolishes the production of hepatitis B e-antigen (HBeAg). The purpose of this literature review is to describe the epidemiology of HBeAg-negative CHB (e-CHB) worldwide. A literature search was conducted to identify studies pertaining to e-CHB and underlying variants (precore and core promoter). Fifty studies were included in our analysis. The median prevalence of e-CHB among patients with chronic HBV infection was 33% in the Mediterranean, 15% in Asia Pacific, and 14% in the USA and Northern Europe. The pre core stop codon variant was detected in a median of 60% (range 0–100%) of HBeAg-negative patients overall, 92% in the Mediterranean, 50% in Asia Pacific and 24% in the USA and Northern Europe. There were very few data on the prevalence of core promoter variants outside Asia where the median prevalence among HBeAg-negative patients was 77%. This literature review revealed that e-CHB is more common than previously suspected and that it is present worldwide with marked variations in the prevalence of associated HBV variants across different geographical regions. Additional research using population based samples of adequate size based on a consensus definition of e-CHB and using standardized HBV DNA assays is needed to better estimate the true prevalence of e-CHB and its associated HBV variants. [ABSTRACT FROM AUTHOR]

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-α (IFN-α) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-α achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30%... [ABSTRACT FROM AUTHOR]

The roles of genetic heterogeneity of the hepatitis B virus (HBV) precore gene in the pathogenesis of HBV infection are unclear. Various methods have been used to detect nucleotide (nt) 1896 precore mutants. We established a new primer-extension assay to facilitate the detection of these mutants. This assay is based upon the fact that there is no adenine in the distal precore region of wild-type HBV. Polymerase chain reaction (PCR)-amplified template DNA was denatured and annealed to the [γ-32P]-labelled primer. During primer extension in the presence of DNA polymerase and dCTP, dGTP, dTTP and ddATP, the reaction terminates if there is a nucleotide A. When mixtures of different ratios of wild-type and nt 1896 precore mutants were analysed in the primer-extension assay, correlation between the percentage known amounts and the percentage measured amounts of nt 1896 precore mutants was excellent (r2=0.9669). When the primer-extension assay and direct sequencing were compared in hepatitis B e antigen (HBeAg)-positive and -negative chronic active hepatitis B patients, the primer-extension assay detected a greater number of nt 1896 precore mutants than direct sequencing and thus most HBV infections were found to be mixed infections. In conclusion, the primer-extension assay is a reliable and sensitive method for the detection of nt 1896 precore mutants. [ABSTRACT FROM AUTHOR]