Data derived from population, case-control, and cohort studies conducted in several Euro-Mediterranean and African countries disclose impressive similarities in the age and modes of hepatitis B virus ...(HBV) transmission and in the prevalence, duration, and outcome of the four phases of the natural history of chronic infection. Perinatal HBV infection is rare while the vast majority of chronic infections originate from horizontal HBV transmission to infants and children. HBeAg loss and seroconversion to anti-HBe occur in a few years time, usually during the second decade of life. HBeAg-negative/anti-HBe-positive chronic hepatitis B (CHB), predominates in these countries being 7–9 times more frequent than HBeAg-positive CHB. The predominance of HBeAg-negative CHB is largely linked to the molecular characteristics of HBV genotype D prevailing in European and African countries of the Mediterranean basin and of genotype E and subgenotype A1 that prevail in the other parts of Africa. The molecular characteristics of the African subgenotype A1 differ from those of European subgenotype A2 explaining the fact that patients infected subgenotype A1 demonstrate an earlier loss of HBeAg and seroconversion to anti-HBe during the natural course of HBV infection compared to those infected with subgenotype A2. It is proposed that the molecular characteristics of HBV genotypes and subgenotypes prevailing in Euro-Mediterranean and African countries acting in concert with host and environmental factors largely determine the natural history of chronic HBV infection and its significant differences from countries of HBV genotype C and B and of subgenotype Ae predominance. The knowledge of the natural history of chronic HBV infection in Euro-Mediterranean and African countries combined with wide screening programs for prompt recognition and treatment of chronic HBV infection both in its HBeAg-positive and -negative immune reactive phases can be expected to increase the efficacy of current and future therapeutic strategies.
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.
We studied the long‐term efficacy of adefovir dipivoxil (ADV) treatment in 42 HBeAg‐negative patients with chronic hepatitis B (CHB) who had developed genotypical lamivudine (LAM) resistance with ...virological and clinical breakthroughs under long‐term LAM treatment. Patients were allocated in 2 treatment groups. In the first (n = 14), LAM was switched to ADV monotherapy whereas in the second (n = 28) ADV was added to LAM. The two groups did not differ in patients' characteristics, all of them having HBV genotype D infection with the precore stop codon mutation. Within 12 months from start of ADV treatment, serum HBV DNA became nondetectable and ALT normalized in 71% and 90% of patients, respectively, with no difference between the 2 arms. Patients with baseline HBV DNA levels less than 107 copies/ml experienced a significantly earlier and more frequent decline in serum HBV DNA to nondetectable levels as compared with patients with greater than 107 HBV DNA copies/ml at baseline (P = 0.0013) This response has hitherto been maintained (median treatment duration 40 months) in all patients with ADV added to LAM, whereas virological and biochemical breakthroughs due to development of ADV signature resistance mutations occurred in 3 of 14 patients (21%) on ADV monotherapy 15 to 18 months from start of treatment (P = 0.0174). Conclusion: Adding ADV to LAM in HBeAg‐negative CHB patients with LAM resistance effectively suppresses HBV replication in most of them and induces biochemical remission that can be maintained in all of them at least for 3 years without any evidence of development of resistance to ADV. (HEPATOLOGY 2007;45:307–313.)
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.
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.
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) log
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) log
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.
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.
Background & Aims The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as ...undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR. Methods A retrospective analysis of 1383 patients, encompassing genotypes 1–4, treated with peginterferon alfa-2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis. Results RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1–4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97–7.52) for predicting SVR in multiple logistic regression analysis of these factors. Conclusions Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B evolves in the natural history of chronic hepatitis B virus (HBV) infection linked with selection of nonproducing HBeAg but ...replication-competent HBV mutants, and may have a potentially severe and progressive course. Effective suppression of HBV replication is the main therapeutic target. Sustained off-therapy responses are rare with treatment of finite duration, except perhaps for interferon-based therapies, which induce such responses in a sizeable, yet small proportion of patients. Eventually, the majority of patients will be treated with long-term oral antiviral therapy, which improves patients' outcome but is associated with progressively increasing rates of viral resistance. The long-term resistance profile of adefovir is significantly better than that of lamivudine (LMV), whereas data for entecavir currently are limited to 2 years, with resistance developing in LMV-resistant but not in treatment-naïve patients. Combination therapy with adefovir added to LMV in LMV-resistant patients is extremely effective; cases of adefovir-resistance have not been reported to date.
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 ⩽10,000 cp/ml (1786 IU/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 (<400 IU/ml), B (<50 IU/ml), C (<75 IU/ml), and D (<1000 IU/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.
HBeAg-negative CHB has now a worldwide distribution, developing in the course of HBeAg-positive chronic HBV infection during or after the phase of HBeAg loss and its seroconversion to anti-HBe. It is ...caused by replicating noncytopathic HBV mutants either unable to produce HBeAg (precore mutants) or with down-regulated transcription of the precore/core messenger RNA (BCP mutants). The most frequently encountered and stable HBeAg-negative mutants in the world are those with a novel translational precore stop codon. They are HBV genotype determined and become selected in genotypes B, C, D, and E (non-A genotypes). They prevail in South Europe, the Mediterranean basin, and Asia, whereas they are rather infrequent in the United States. The incidence of HBeAg-negative CHB is increasing in the world. The selection of HBeAg-negative HBV mutants is determined both by viral and host factors, the same being true for their ability to replicate in the presence of anti-HBe immunity. Clinical, virologic, and biochemical features as well as the natural course of HBe-negative CHB have been reviewed, and the efficacy of IFN-
α and lamivudine therapy as well as the problem of viral resistance to lamivudine have been critically presented.
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for viral persistence in the natural course of chronic HBV infection and during prolonged antiviral therapy and serves ...as the template for the production of HBV pregenomic RNA (pgRNA), the primary step in HBV replication. In this study, we have developed and applied sensitive and specific quantitative real‐time polymerase chain reaction (PCR) assays for the measurement of intrahepatic concentration, pgRNA production, and replicative activity of cccDNA in liver biopsy samples from 34 non‐treated patients with chronic hepatitis B (CHB); 12 hepatitis B e antigen (HBeAg)(+) and 22 HBeAg(−). Median copy number for cccDNA was 1.5 per cell and for pgRNA significantly higher, 6.5 copies per cell, with a good correlation between cccDNA and pgRNA levels in all samples. In HBeAg(−) patients, median values of cccDNA and pgRNA levels were 10‐fold and 200‐fold lower than in HBeAg(+), respectively, reflecting the differences in viral activity and clinical characteristics of the two groups. Furthermore, the replicative activity of intrahepatic cccDNA was significantly lower in HBeAg(−) patients harboring mutant HBV strains than in HBeAg(+) patients: median 3.5 versus 101 pgRNA copies per cccDNA molecule. In conclusion, the levels of both HBV cccDNA, a marker of HBV persistence, and pgRNA, an indicator of viral replication, in the liver of chronically infected patients correlate with viral activity and the phase of HBV infection. The combined measurement of cccDNA and pgRNA levels provides valuable information on the presence and replicative activity of intrahepatic HBV cccDNA. (HEPATOLOGY 2006;44:694–702.)
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