Serum hepatitis B virus RNA detectability, composition and clinical significance in patients with ab initio hepatitis B e antigen negative chronic hepatitis B.

BACKGROUND: Serum hepatitis B virus (HBV) RNA is a surrogate biomarker for intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity and persistence. In this retrospective study, we investigated its presence, levels and composition in ab initio Hepatitis B e antigen (HBeAg) negative chronically infected patients and examined possible associations with disease activity and the outcome of nucleos(t)ide analogue (NA) discontinuation. METHODS: We developed a sensitive real time polymerase chain reaction (RT-PCR) for the specific detection of HBV pregenomic RNA (pgRNA) and precore (preC) mRNA and analyzed 220 serum specimens, 160 under NA treatment, from 116 Greek patients initially negative for HBeAg. RESULTS: HBV pgRNA was detected in 31% and preC mRNA in 15% of samples, at lower levels representing a small fraction (3.4%) of total core promoter produced transcripts. In the absence of NAs, pgRNA was detected in 57% of samples with median value of 5.19 (2.61-8.35) log10 cp/mL, at lower levels than HBV DNA and correlated significantly with ALT (r = 0.764) and serum HBV DNA (r = 0.906). A wide range of HBV DNA/pgRNA ratio was observed with significant inter- and intra-patient variation. During NA treatment, pgRNA displayed low detectability (22%) and variable levels, median 3.97 (2.30- 8.13) log10 cp/mL, as well as, a significant inverse correlation with the duration of treatment (r = - 0.346, p < 0.01). In 74 events of NA discontinuation, end-of-treatment pgRNA-positive compared to pgRNA-negative cases, experienced more frequently virological (p = 0.016) and clinical (p = 0.011) relapse. CONCLUSIONS: In genotype D ab initio HBeAg negative patients, serum HBV RNA is primarily composed of pgRNA plus a minor fraction of preC mRNA transcripts. Serum pgRNA is associated with disease activity, suggesting lysis of infected hepatocytes as a possible source of serum HBV RNA in untreated patients and in the early phase of NA treatment. During long term NA treatment, detectable serum pgRNA predicts viral rebound and clinical relapse following treatment discontinuation and may thus serve as a marker for the decision of cessation of therapy.

Hepatocellular carcinoma after treatment cessation in non-cirrhotic HBeAg-negative chronic hepatitis B: A multicentre cohort study.

BACKGROUND AND AIMS: Scarce data exist on the effect of nucleos(t)ide analogue (NA) discontinuation on hepatocellular carcinoma (HCC) risk in HBeAg-negative chronic hepatitis B (CHBe-). Therefore, we assessed whether HCC risk is increased in non-cirrhotic CHBe- patients who discontinue compared to those remaining on NAs. METHODS: This cohort study included 650 consecutive non-cirrhotic Caucasian or Asian patients with CHBe- without a history of HCC who discontinued NAs after a median of 5 or 3 years (cases, n = 325; Caucasians: 143, Asians: 182) or remained on NA therapy beyond 5 or 3 years respectively (controls, n = 325; Caucasians: 223, Asians: 102). Propensity score (PS) 1:1 matching was applied to adjust for patients' origin, age and sex. RESULTS: During a median follow-up of 44 months, HCC developed in 7/325 cases and 9/325 controls or 7/245 PS-matched cases and 7/245 PS-matched controls with 5-year cumulative HCC incidence of 5.1% and 4.9% respectively (log-rank, P = .836). No difference in 5-year HCC risk was observed between cases and controls of Caucasian (3.0% vs 4.8%; log-rank, P = .510) or Asian origin (1.3% vs 2.2%; log-rank, P = .873). In both cases and controls, HCC incidence was independently associated with age and PAGE-B score. In cases alone, HCC development after NA discontinuation was associated only with pretreatment platelet counts and PAGE-B score, but not with any type of relapse or HBsAg loss. CONCLUSIONS: Our findings suggest that discontinuation of effective long-term NA therapy in non-cirrhotic CHBe- patients are not associated with increased HCC risk, which is not affected by post-NA relapses and/or HBsAg loss.

Current practice and contrasting views on discontinuation of nucleos(t)ide analog therapy in chronic hepatitis B.

Introduction: Long-term, even indefinite treatment with nucleos(t)ide analogs (NAs) is the current first-line therapy for patients with chronic hepatitis B (CHB), regardless of its histological stage. Guidelines and recommendations on duration and endpoints of NA therapy in CHB are not identical and change over time.Areas covered: The authors review NA discontinuation approaches and views with an emphasis on HBeAg-negative patients based on published studies relevant to the topic, stressing on whether or not the optimal endpoint of HBsAg loss is practically achievable.Expert opinion: Discontinuation of NA therapy in HBeAg-negative noncirrhotic patients has to be considered after long-term effective treatment with controlled liver disease activity, undetectable viremia, and significant decline in serum HBsAg titers. Close post-treatment monitoring is required for early intervention in cases of severe clinical relapse. Immediate retreatment hampers the favorable outcome of HBsAg clearance (functional cure) and should be avoided in transient ALT flares. Predictors of such relapses are still under investigation and include viral and patient factors. For HBeAg-positive noncirrhotic patients, there is wide acceptance of the endpoint of HBeAg seroconversion, after a long consolidation period.

Common ABCB1 polymorphisms in Greek patients with chronic hepatitis C infection: A comparison with hyperlipidemic patients and the general population.

BACKGROUND: Hepatitis C virus infectivity and replication efficiency appears to be dependent on the lipid content and organization of the plasma membrane of the host cell, as well as of the intracellular membranous web. As there is increasing awareness of a role played by the efflux pump ABCB1 (p-glycoprotein, P-gp) in lipid homeostasis, its function could be a determinant of chronic HCV infection. The aim of the present study was to examine and compare the distribution of common ABCB1 genotypes in patients with chronic HCV infection (n=168), hyperlipidemic patients (n=168) and a control group (n=173), all from Greece. METHODS: Participants were genotyped for the ABCB12677G>T/A and 3435C>T polymorphisms with previously reported PCR-RFLP methods. Genotype and allele frequency distributions were compared between the three groups with the χ(2) test of independence. RESULTS: The ABCB1 2677GG (ancestral) genotypes were significantly over-represented in patients with chronic hepatitis C compared to controls (39.3% vs. 26.6%, p=0.015 according to the dominant model). A similar result was obtained when hyperlipidemic patients were compared to controls (45.2% vs. 26.6%, p<0.001 according to the dominant model). Comparison of ABCB1 3435C>T genotype and allele distributions provided similar but not as significant differences. Genotype and allele distributions for both ABCB12677G>T/A and 3435C>T were very similar between HCV patients and hyperlipidemic patients. CONCLUSION: Our findings imply an influence of ABCB1 polymorphisms on HCV infectivity, possibly through an effect on lipid homeostasis.

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues.

Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.

Hepatitis B surface antigen quantification in chronic hepatitis B and its clinical utility.

Serum HBsAg levels have been quantified extensively in recent years with simple completely automated assays in the various phases of the natural course of chronic HBV infection, have been compared with cccDNA in the liver, with various markers of HBV replication and have been correlated with several viral, host and environmental variables. Low HBsAg levels in inactive carriers predict a spontaneous HbsAg loss. Quantification of HBsAg in serum at baseline and its decline under interferon-alfa based regimens, both in HBeAg-positive and HBeAg-negative CHB, provides important information on the prediction of sustained post-treatment outcomes and on subsequent HBsAg clearance. The value of HBsAg quantification in the monitoring of long term nucleos(t)ide analogue treatment of CHB and in the prediction of sustained response remains unclear. In this review, the most recent data regarding the overall clinical utility of HBsAg measurement in HBeAg-positive and -negative CHB and in their treatment, is critically presented.

Update on Hepatitis B Virus Infection: Focus on Treatment.

This review article is an update of the current treatment strategies available for chronic hepatitis B. In addition to achieving on-therapy clinical remission and suppression of HBV replication without resistance, the ultimate goal of therapy is the development of sustained remission and HBsAg loss after discontinuation of treatment. This is the closest possible to cure outcome for hepatitis B virus (HBV) infection. These goals can be achieved by response-guided courses of pegylated interferon (peg-IFN)-alpha at rates higher than 30%, both in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Review of the data regarding discontinuation of long term NA treatment in HBeAg-negative patients revealed that stopping such therapy is safe with high rates of sustained off treatment responses that appear to be immunologically induced. Decreasing hepatitis B surface antigen (HBsAg) titers under therapy to <500, particularly <100 IU/mL, and adding a course of peg-IFN to ongoing long term nucleos(t)ide analogue (NA) therapy increase the percentage of sustained responses following discontinuation of NA treatment.

The natural course of chronic hepatitis B virus infection and its management.

Chronic infection with the hepatitis B virus (HBV) runs a long natural course during which underlying changes in liver histology can progress to cirrhosis and hepatic decompensation, as well as to hepatocellular carcinoma. Therapeutic intervention is currently aiming at suppression of HBV replication by applying a number of pharmacological agents. For an optimum use of available therapies, good knowledge of the natural course of chronic infection, as well as of the role played by several viral, host, and environmental factors, is mandatory. The larger part of this chapter deals with how to treat the various subsets of patients with chronic hepatitis B (CHB), using mainly three first-line drugs: pegylated interferon-α2a, entecavir, and tenofovir, administered either in finite courses or indefinitely. The frequency of virological, serological, biochemical, and histological responses in the various subsets of patients, both during and after stopping treatment, is reviewed. It is stressed that the application of the highly potent antivirals entecavir and tenofovir, with acceptable safety records and with a high barrier to HBV resistance, represents major progress in the treatment of CHB. Despite the hitherto important developments in the treatment of viral hepatitis B, clinical cure of chronic HBV infection with HBsAg loss is achievable only in a few treated patients while eradication of HBV infection appears unrealistic. Development of new pharmacological agents acting at multiple targets of the replicative cycle of HBV may achieve higher efficacy and even cure of CHB.

Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype.

BACKGROUND & AIMS: We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a±lamivudine in the Phase III trial. METHODS: All patients (n=230) who participated in long-term follow-up were included according to the availability of HBsAg level measurements. Long-term virological response was defined as HBV DNA ≤ 10,000cp/ml (1786IU/ml) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24, and 72. RESULTS: Baseline HBsAg levels were significantly higher for A than B, C, and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12-24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71%, and 75% for genotypes A (<400IU/ml), B (<50IU/ml), C (<75IU/ml), and D (<1000IU/ml), respectively. CONCLUSIONS: On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.

Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients.

PURPOSE: To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients. METHODS: HBeAg-negative patients received peginterferon alfa-2a (180 µg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment. RESULTS: HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline. CONCLUSIONS: Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.

Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies.

OBJECTIVE: This analysis examines the safety profile of standard- versus high-dose peginterferon alfa-2a. METHODS: Data were pooled from five trials including HCV genotype 1- or 4-infected naive and treatment-experienced patients (n = 2,940). Patients were randomized to receive peginterferon alfa-2a at 180 µg/week (standard-dose; n = 1,672) or 360 µg/week (high-dose; n = 1,268) plus ribavirin 1,000/1,200 mg/day for 12 weeks; after 12 weeks, all received standard dose. This safety analysis was restricted to the first 12 weeks. RESULTS: In standard and high-dose groups, similar frequencies of serious adverse events (SAEs, 3.2 and 4.2%, respectively) and treatment discontinuations for safety reasons (2.8 and 2.9%) were reported. More patients reported weight decrease as an adverse event (AE) in the 360 µg/week group (7.7 vs. 3.3%). Significant (p < 0.05) independent predictors for discontinuation due to safety were older age, male gender, lower albumin and low neutrophil count, but not the starting dose of peginterferon alfa-2a. Although more laboratory abnormalities were reported in patients receiving high-dose peginterferon alfa-2a, this was not reflected in AEs or discontinuations, suggesting these are adequately managed by dose modification. CONCLUSIONS: High-dose peginterferon alfa-2a for 12 weeks does not significantly increase the incidence of SAEs or discontinuations for safety reasons, beyond that of a standard dose regimen.

Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.

BACKGROUND & AIMS: Little is known about the biochemical and virological effects of stopping long-term nucleos(t)ide analogue therapy for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). METHODS: We performed a cohort observational study, following 33 HBeAg-negative patients with CHB, undetectable serum HBV DNA, and normal levels of aminotransferases after long-term (4 or 5 years) treatment with adefovir dipivoxil (ADV). All patients were followed for 5.5 years; follow-up visits included measurements of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and HBV DNA monthly for the first 6 months and every 3-6 months thereafter. Various factors were measured at baseline, the end of treatment (EOT), and following treatment to identify those associated with clearance of HBsAg. RESULTS: During the first few months of the postdiscontinuation period, all patients experienced virological and 25 (76%) had biochemical relapse. During the follow-up period, 18 patients (55%) who had discontinued antiviral therapy achieved sustained response (HBV DNA level <2000 IU/L, persistently normal level of ALT). Among these, 13 (72%) cleared HBsAg. Fifteen patients (45%) with virological and/or biochemical relapse were re-treated with oral antiviral agents (11 during the first 18 months and 4 after the third year), without evidence of liver decompensation; only 1 lost HBsAg (6%). Higher pretreatment and EOT levels of ALT, no previous treatment with interferon, and lower level of HBsAg at the EOT were significantly associated with HBsAg clearance based on multivariate analysis. CONCLUSIONS: In HBeAg-negative patients with CHB, it is safe and effective to discontinue ADV therapy after 4 or 5 years; 55% of patients have sustained responses, and 39% of patients lose HBsAg.

Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.

BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin.

BACKGROUND & AIMS: It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of treatment influences the probability of achieving a sustained virological response (SVR) in patients without a week 4 rapid virological response (RVR). METHODS: Data were retrospectively analyzed from two studies in which treatment-naive patients received peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1000/1200 mg/day for 48 weeks. Five hundred and fifty-eight genotype 1 patients with evaluable HCV RNA at baseline and week 4 were grouped according to RVR status: RVR (HCV RNA<50 IU/ml) or no RVR. Non-RVR patients were subdivided into discrete mutually exclusive categories according to week 4 HCV RNA; the proportion of patients with undetectable HCV RNA at week 12 was calculated per each category, and among them, the proportion with an SVR. RESULTS: Overall, 88% of RVR patients and 43% of non-RVR patients achieved an SVR (p<0.0001). Among non-RVR patients, SVR rates were 77%, 61%, 43%, 27% and 13%, respectively (trend test p<0.0001) in those with unquantifiable HCV RNA or ≥ 3 log(10), ≥ 2 log(10), ≥ 1 log(10), or<1 log(10) drop to week 4. In patients HCV RNA positive at week 4, SVR rates were 67% for those negative at week 12 vs. 17% (HCV RNA positive patients or who had missing values at week 12 [p<0.0001]). CONCLUSIONS: The probability of achieving SVR is graded in relation to the magnitude of reduction in HCV RNA at week 4 and 12. Patients with a ≥ 3 log(10) drop in HCV RNA at week 4 have a high probability of achieving an SVR.

Treatment of special populations with chronic hepatitis B infection.

All therapeutic agents that are currently in use for the treatment of chronic hepatitis B have been administered to a large number of patients in clinical trials in order to be approved as efficacious and safe. Nevertheless, in these trials, many patients have been excluded either because they have decompensated cirrhosis, or they belong to groups with comorbidities that can seriously affect the underlying liver disease, or where the treatment for chronic hepatitis B virus infection can be contraindicated. Such groups of patients are those with hepatitis D virus, hepatitis C virus and HIV coinfections, patients who have undergone transplantation or are immunosuppressed due to chemotherapy or other treatment, patients with end-stage renal disease under dialysis, acute and fulminant hepatitis B and also, children and pregnant women. In this article, all of the aspects of treatment of these special categories are discussed, since for many of these patients, treatment is of a greater importance compared with the standard patient with chronic hepatitis B, and in real life they represent a great percentage of chronic hepatitis B virus infection patients.

Effect of antiviral therapy on the immunohistochemical expression of bcl-xL and bax protein in patients with HBeAg-negative chronic hepatitis B.

The effect of antiviral treatment on apoptosis in chronic hepatitis B (CHB) has not been clarified. We evaluated the hepatic immunohistochemical expression of the pro-apoptotic bax and the antiapoptotic bcl-xL protein in HBeAg-negative CHB patients before and after treatment. In our study we included 72 paired biopsies from 36 HBeAg-negative CHB patients: 29 treated (interferon-alfa: 17, adefovir: 12) and 7 untreated. Changes in expression of apoptotic proteins (D-bax, D-bcl-xL), necroinflammation and fibrosis (D-grade/D-stage) (Ishak classification) were evaluated. We found that Bax-positive compared to bax-negative biopsies had worse necroinflammation (8.2 vs. 6.7, P = 0.05) and fibrosis score (3.9 vs. 3, P = 0.036). bcl-xL-positive compared to bcl-xL-negative biopsies had lower intralobular inflammation (1.6 vs. 2.2, P = 0.03). Decreased compared to stable/increased D-bax was associated with greater improvement in necroinflammation only in treated patients (D-grade: -4.6 vs. -1.6, P = 0.05) and greater fibrosis improvement in interferon treated patients (D-stage: -0.4 vs. 0.55, P = 0.05). Increased compared to stable/decreased total apoptotic trend [D-apoptosis: (D-bax)-(D-bcl-xL)], was associated with worsening fibrosis, particularly in adefovir treated patients (D-stage: 2.3 vs. 0, P = 0.004). In the 11 patients without significant changes from 1st to 2nd biopsy, increased apoptosis was more frequent in treated than untreated cases (P = 0.046). In multivariate analysis, bax change was independently associated with change of grade (P = 0.038) and antiviral therapy (P = 0.015). In conclusions, in HBeAg-negative CHB, histological improvement after treatment is associated with decreased hepatocyte apoptosis. In patients without substantial histological changes, treatment seems to increase the apoptosis of hepatocytes, thus having a possible protective effect on hepatocarcinogenesis.

Management of hepatitis C virus genotype 4: recommendations of an international expert panel.

HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.

Milestones and perspectives in viral hepatitis B.

There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in identifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.