Hepatitis B E Antigen Seroconversion Rate Research Articles

No Benefit to Continue Lamivudine Therapy after Emergence of Ymdd Mutations

Mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rt M 204 I/V) may develop after 6-9 months of lamivudine therapy. The current practice of continuing lamivudine therapy has been associated with hepatitis flares or even hepatic decompensation. In addition, experiments have shown that the defective replication competency of rt M 204 I/V restores upon addition of lamivudine. To evaluate whether continuing lamivudine therapy after emergence of rt M 204 I/V is appropriate. The clinical courses of 66 patients with continuing lamivudine therapy (continued group) and 68 patients who discontinued lamivudine therapy (discontinued group) were monitored monthly or more frequently if condition required. Hepatitis flare, jaundice, hepatic decompensation and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive patients were documented as events. In a 12-month period, hepatitis flares and decompensations occurred in 67 and 11%, respectively, in patients who continued lamivudine therapy, as compared with 54 and 7%, respectively (P>0.05), in those who stopped therapy. HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group (P=0.08). Serum HBV DNA increased in 48 (73%) of the continued group, and the median level increased from 46 pg/ml upon first detection of mutation to 330 pg/ml (P<0.001) at the end of 12 months continuing therapy. In contrast, serum HBV DNA level in the discontinued group increased in 22 (33%) patients but decreased in 39 patients, and median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping lamivudine. These results suggest that there is no benefit to continued lamivudine therapy after emergence of rt M 204 I/V.

Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil

Background & aims: Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of adefovir dipivoxil. Antiviral efficacy of adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race. Methods: HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694). Results: Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Conclusions: HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.

Clinical features of hepatitis B virus genotype A in Japanese patients.

Hepatitis B virus (HBV) genotype A is predominant in northern Europe and central Africa. In the present study, we examined the clinical features associated with HBV genotype A disease in the Tokyo metropolitan area. We investigated 53 cases of HBV surface antigen (HBsAg)-positive Japanese patients with HBV genotype A. The 53 cases were further classified as to their serum alanine aminotransferase (ALT) status being within the normal range (asymptomatic carriers, n = 17), chronic hepatitis (n = 15), liver cirrhosis (n = 4), and acute hepatitis (n = 17). Chronic hepatitis patients had significantly higher HBV DNA levels (P = 0.003) and hepatitis B e antigen (HBeAg) positivity rates at the initial visit than did asymptomatic carriers or patients with liver cirrhosis (P = 0.003 and P = 0.054, respectively). The efficacy of treatment (HBeAg seroconversion rate) was 75% in 12 chronic hepatitis patients, which was excellent. A family history of HBsAg positivity was identified in eight (15%) families (five asymptomatic carriers, three with chronic hepatitis). However, none of the mothers in the study was positive for HBV genotype A. Maternal transmission of HBV has often been reported in Japan, but our present findings suggest that horizontal infection of HBV genotype A is more prevalent in the Tokyo metropolitan area. Our data indicate that HBV genotype A exhibits a mode of infection different from that of conventional HBV previously seen in Japan.

Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma

The pathologic role of hepatitis B virus (HBV) genotype in Chinese patients with HBV infection is largely unknown. We examined the relationship between HBV genotypes, and hepatitis B e antigen (HBeAg) seroconversion, acute exacerbation, cirrhosis-related complications, and precore/core promoter mutations. Three hundred forty-three HBV patients (288 were asymptomatic, 55 presented with cirrhosis-related complications) were recruited. HBV genotypes and precore/core promoter mutations were determined by line probe assays. Genotypes B and C were the 2 most common genotypes, contributing 28% and 60%, respectively. The median age of HBeAg seroconversion for patients with genotype B was 9 years earlier than patients with genotype C ( P = .011). There were no differences in the liver biochemistry, HBV DNA level, and cumulative risk of acute exacerbation (defined as increased alanine aminotransferase level ≥1.5 × upper limit of normal) between patients with genotypes B and C. There was a trend for patients with genotype B to have a higher cumulative rate of HBeAg seroconversion compared with patients with genotype C at the initial follow-up of 6 years ( P = .053), but this difference became insignificant during subsequent follow-up. The prevalence of both genotypes was the same in patients with and without cirrhosis-related complications and/or hepatocellular carcinoma. Genotype B was associated with precore mutations ( P < .0001), whereas genotype C was associated with core promoter mutations ( P < .0001). In conclusion, although patients with genotype B had earlier HBeAg seroconversion, there was no significant reduction in the risk of development of complications. Genotypes B and C are associated with high prevalence of precore and core promoter mutations, respectively. (H EPATOLOGY 2003;37:562-567.)

Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. This prospective open study reports the results of lamivudine treatment in children with chronic hepatitis B infection who did not respond to previous interferon treatment. Lamivudine, 3 mg/kg/day (maximum, 100 mg/day), was given for 52 weeks to 20 children and adolescents, ages 8.5 to 19 years, with chronic hepatitis B infection who had been treated with interferon 2 to 5 years earlier. We evaluated virologic and biochemical responses, the occurrence of YMDD mutants and adverse effects. All children were HBV DNA+, hepatitis B e antigen (HBeAg) /anti-hepatitis B e antibody- at start of treatment. At the end of 1 year, HBV DNA declined by 95% in all patients, and 8 of 18 (44%) had sustained undetectable HBV DNA by hybridization assay. Median pretreatment alanine aminotransferase (ALT) x1.5 upper limit of normal decreased to ALT x0.9 upper limit of normal after 1 year. One child became HBeAg-negative. YMDD mutants were detected in 11 of 17 (65%) children after 1 year of lamivudine treatment. Among children with YMDD mutant variants, 54% maintained normal ALT values and 45% had undetectable HBV DNA by hybridization assay. No adverse effects were observed. Children with chronic hepatitis B infection treated with lamivudine after failure of interferon therapy had decreased HBV replication and improved ALT values. However, lamivudine treatment resulted in an exceptionally high rate of lamivudine-resistant mutants and low HBeAg seroconversion rate.

Hepatitis B Genotypes in Chronic Hepatitis B and Lamivudine Therapy

The influence of hepatitis B virus (HBV) genotypes on the natural history and the response to treatment of patients with chronic hepatitis B are of potential interest. Compared to the patients with HBV genotype C, those with genotype B were of a younger age and had a higher cumulative rate of hepatitis B e antigen (HBeAg) seroconversion during the initial 6 years of follow-up. The earlier HBeAg seroconversion in the patients with genotype B, however, did not provide them with a benefit in terms of a reduced risk of developing long-term complications. The response to lamivudine therapy was evaluated in 21 patients infected with HBV genotype B (all of subtype Ba) and 61 with genotype C. There were no differences in the virological response to lamivudine therapy, based on the reduction in median logarithmic HBV DNA titer as well as alanine aminotransferase (ALT) levels, normalization of ALT and the rate of HBeAg seroconversion between the patients with genotypes B and C. No differences were noted either, in the frequency of YMDD mutants at week 52 or the cumulative risk of HBV DNA breakthroughs with YMDD mutations during long-term lamivudine therapy (median 37.5 months). In conclusion, there is no influence of HBV genotypes on the development of long-term complications and lamivudine therapy in Hong Kong.

Short-Term Lamivudine Therapy in Patients with Chronic Hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 × upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184–2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3–14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5–25,903 pg/ml). After a median of 8.2 months (3–15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 × ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 × ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response.

Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C

Background & Aims: Recent studies suggest that hepatitis B virus (HBV) genotype B is associated with less active liver disease than HBV genotype C. The aim of our study was to determine if HBV genotype B is associated with higher rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion compared with genotype C. Methods: A retrospective study using stored sera from 332 Chinese patients with chronic HBV infection followed for a mean of 48 months (range, 12–98) were tested for HBV genotype using a line-probe assay. Results: HBV DNA was detected in 273 patients, 122 had HBV genotype B and 147 genotype C. Patients with genotype B had a significantly lower prevalence of HBeAg at presentation and significantly higher rates of spontaneous HBeAg seroconversion during follow-up. HBV genotype B patients who were HBeAg positive were significantly younger, and spontaneous HBeAg seroconversion occurred approximately 1 decade earlier compared with HBV genotype C patients. Multivariate analyses identified high alanine aminotransferase (baseline and follow-up), age >30 years, and genotype B as independent factors associated with spontaneous HBeAg seroconversion. Conclusions: HBV genotype B is associated with earlier HBeAg seroconversion than genotype C. This finding may explain the less active/progressive liver disease in patients with genotype B.GASTROENTEROLOGY 2002;122:1756-1762

Management of patients with chronic hepatitis B.

Better understanding of hepatitis B virus (HBV) replication and the natural history and immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action, is the basis for better therapeutic strategies against chronic hepatitis B. Substantial experience has now been accumulated in the use of some of these drugs, and an Asia-Pacific Consensus has been reached on indications for their use. The goals of therapy and aspects of general management will be reviewed here. Among currently available drugs, alpha-interferon therapy gives a response rate (hepatitis B e antigen (HBeAg) seroconversion) of 30-40% compared with 10-20% in matched controls, but patients with lower alanine aminotransferase (ALT), higher HBV-DNA, and immunosuppressed patients have a poorer response, and alpha-interferon can be dangerous in cirrhosis. Meta-analysis of four controlled trials also suggests that thymosin-alpha1 is effective, but more studies are needed. Lamivudine has been most extensively studied. It is effective in terms of HBV-DNA loss, ALT normalization, HBeAg seroconversion, and improvement in histology, as well as being well tolerated. After 1 year of treatment, HBeAg seroconversion rate increased with higher pretherapy ALT levels, suggesting that patients with stronger endogenous antiviral defenses to kill hepatocytes harboring covalently closed circular DNA have a better response to direct antiviral effects. Lamivudine is also beneficial in HBeAg negative chronic hepatitis B, and patients with decompensated cirrhosis and HBV replication. However, genotypic-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations start to emerge after 9-10 months of lamivudine therapy, and their incidence increases more quickly than the HBeAg seroconversion rate durating prolonged therapy. Thus the benefits of long-term lamivudine must be balanced against concern about YMDD mutations, and the durability of treatment response. There are encouraging preliminary results for adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/nucleotide analogs in the early stages of appraisal; entecavir and adefovir dipivoxil appear effective in patients with YMDD mutants. Further development of new drugs and new strategies, such as combination or sequential therapy, may help to better achieve the goals of treatment for chronic hepatitis B in the new century.

Treatment of chronic hepatitis B: case selection and duration of therapy.

Treatment of chronic hepatitis B: case selection and duration of therapy.

Efficacy of interferon alfa and lamivudine combination therapy versus interferon alfa monotherapy in Turkish patients with chronic hepatitis B: A double-blind, randomized, comparative study

Background: Interferon (IFN) alfa and lamivudine are the most effective agents used in the treatment of chronic hepatitis B virus (HBV). Monotherapy with IFN alfa or lamivudine provides significant benefit, but the combination of these drugs is still under investigation. It has been suggested that combination therapy has some advantages over monotherapy. Objective: The purpose of this study was to evaluate the efficacy of concurrent combination therapy with lamivudine and IFN alfa versus IFN alfa monotherapy in previously untreated patients with chronic HBV. Method: Patients were randomly assigned to 6 months' therapy with IFN alfa 9 million units 3 times weekly alone or in combination with 100 mg/d oral lamivudine. Alanine aminotransferase (ALT) measurements and viral load assessments (HBV DNA level as measured by polymerase chain reaction) were performed at baseline and months 6 and 12. Levels of hepatitis B e antigen (HBeAg) and anti-HBeAg were determined at baseline and at the end of treatment (month 12). Knodell histologic activity index score was determined at baseline. Results: Fifty patients were enrolled in each group. ALT normalization rates in the monotherapy and combination therapy groups, respectively, were 56% and 86% ( P < 0.05 between groups) at month 6, and 48% and 64% at month 12 ( P < 0.05 between groups). In the monotherapy and combination groups, respectively, there were 21 (42%) and 24 (48%) complete responders ( P < 0.05); 5 (10%) and 10 (20%) partial responders ( P < 0.05); and 24 (48%) and 16 (32%) nonresponders ( P < 0.05). HBeAg seroconversion rates were 22% in the monotherapy group and 30% in the combination therapy group at the end of 12 months ( P = NS between groups). Conclusion: Concurrent combination therapy with IFN alfa and lamivudine has a more beneficial effect on biochemical parameters (ie, ALT levels) than on viral parameters (ie, HBV DNA, seroconversion to anti-HBeAg) and this effect is more pronounced after 1 year of treatment than after 6 months. Further studies are needed to determine the long-term effects of combination therapy with lamivudine and IFN alfa.

Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: Results after 3 years of therapy

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe–positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2× upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy. (HEPATOLOGY 2001;33:1527-1532.)

Management of Chronic Hepatitis B

According to the WHO, approximately 350 million people have chronic hepatitis B. Individuals with chronic hepatitis B have a highly variable and unpredictable clinical course and are at risk for developing cirrhosis and hepatocellular carcinoma. Lamivudine is the only oral antiviral agent approved for the treatment of patients with chronic hepatitis B. Lamivudine is useful in a wide range of patients with chronic hepatitis B and ongoing viral replication. In patients with compensated liver disease treated for 52 weeks in multicenter randomized, double-blind clinical studies, lamivudine 100 mg/day inhibited hepatitis B virus (HBV) replication, normalized ALT levels, produced significant reductions in hepatic necroinflammatory activity and halted the progression of fibrosis compared with placebo. Hepatitis B e antigen (HBeAg) seroconversion rates were also increased during treatment with the drug compared with placebo. In patients who continued to receive the drug after the completion of these trials, improvements in liver histology were maintained and HBeAg seroconversion rates increased in proportion to the duration of treatment. Pretreatment ALT levels were predictive of HBeAgseroconversion. In patients with baseline ALT levels ≥2-fold higher than the upper limit of normal, seroconversion rates were significantly higher than in those with lower baseline values. Data from 2 randomized studies indicate that sequential therapy with lamivudine for 8 weeks and then lamivudine plus interferon-α for 16 weeks provides no greater benefit than that of monotherapy with lamivudine for 52 weeks or interferon-α for 16 weeks. According to data from noncomparative studies, lamivudine 100 or 150 mg/day resulted in clinical stabilization, significant reductions in Child-Pugh-Turcotte scores and loss of HBeAg in many patients with decompensated liver disease. Moreover, some patients have been placed on inactive status for liver transplantation after treatment with the drug. Lamivudine-resistant HBV variants have been isolated from patients with chronic hepatitis B during treatment with lamivudine. The prevalence of these variants increases with the duration of treatment; however, their long term clinical significance has not been established. Lamivudine is well tolerated. The frequency of adverse events in lamivudine or placebo recipients was similar in a pooled analysis of clinical trial data. Nonetheless, patients must be monitored for the emergence of lamivudine-resistant variants and elevated liver enzyme levels (ALT flares). In a series of economic models, use of lamivudine was predicted to reduce the cost per case of cirrhosis prevented and increase mean life expectancy compared with use of interferon-α in the US. Other analyses, which incorporated a fixed drug budget scenario, concluded that use of lamivudine would increase the number of successfully treated patients by 2- to 3-fold compared with interferon-α, because of lower acquisition costs. In conclusion, lamivudine is useful in a wide range of patients with chronic hepatitis B and ongoing viral replication.

Combined Interferon and Lamivudine Therapy: Is This The Treatment of Choice for Patients With Chronic Hepatitis B Virus Infection?

Background, aim and methods-Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferonlamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n = 75); alpha interferon 10 million units three times weekly for 16 weeks (n = 69); or lamivudine 100 mg daily for 52 weeks (n = 82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). Results-The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p = 0.12 and p = 0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively, p = 0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. Conclusions-HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Combination therapy with lamivudine and famciclovir for chronic hepatitis B–infected Chinese patients: A viral dynamics study

In vitro studies have shown that lamivudine and penciclovir (the active metabolite of famciclovir) act synergistically to inhibit hepatitis B virus (HBV) replication. We compared the effectiveness of HBV viral suppression by lamivudine monotherapy versus lamivudine plus famciclovir combination therapy in Chinese patients with chronic HBV infection. Twenty-one Chinese hepatitis B e antigen (HBeAg)-positive patients, with detectable HBV DNA (Digene Hybrid Capture II), were randomized to receive either lamivudine 150 mg/d orally (group 1, 9 patients) or lamivudine 150 mg/d plus famciclovir 500 mg 3 times a day orally (group 2, 12 patients) for 12 weeks, with a follow-up period of at least 16 weeks. Serial serum HBV-DNA levels were determined and a mathematical model with provision for incomplete inhibition of virus production during therapy was applied to analyze the dynamics of viral clearance. The mean antiviral efficacy was significantly greater in group 2 than in group 1 (0.988 ± 0.012 vs. 0.94 ± 0.03, P = .0012). HBV DNA returned to pretreatment level within 16 weeks after the end of initial treatment in 4 patients (66.7%) in group 1 and none in group 2 (P = .08), who remained HBeAg positive and received no further treatment after week 12. Hence, in Chinese chronic HBeAg-positive patients, combination therapy using lamivudine and famciclovir was superior to lamivudine monotherapy in inhibiting HBV replication. Further studies of longer duration are needed to define whether combination therapy will increase the HBeAg seroconversion rate and decrease the rate of emergence of lamivudine-resistant variants. (Hepatology 2000;32:394-399.)

Natural history of hepatitis B virus infection in children.

Hepatitis B virus (HBV) infection during childhood can cause acute, fulminant or chronic hepatitis, liver cirrhosis, and liver cancer. Approximately 90% of the infants of hepatitis B e antigen (HBeAg) seropositive mothers become hepatitis B surface antigen (HBsAg) carriers. Children chronically infected are mostly asymptomatic. Although liver damage is usually mild during childhood, severe liver disease, including cirrhosis and hepatocellular carcinoma, may develop insidiously for 2-7 years. Spontaneous HBeAg seroconversion occurs gradually as the age of the child increases. Viral replication is reduced during this process, which is usually preceded by an elevation of aminotransferases. In a long-term follow-up study, the annual HBeAg seroconversion rate was 4-5% in children older than 3 years of age and less than 2% in children under 3 years. The annual seroconversion rate of HBsAg was very low (0.56%). Age at infection, maternal HBsAg and HBeAg status, host immune status, and possibly the HBV strain are the main factors determining the course of HBV infection in children.

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

BACKGROUND, AIM, AND METHODSAlpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside...

Chronic hepatitis virus infection in children.

Hepatitis B and C viruses (HBV and HCV) are the two main hepatitis viruses causing chronic liver diseases in children. In hyperendemic areas, nearly half of the primary infection in chronic HBV carriers occurs during the perinatal period through the transmission from hepatitis B e antigen (HBeAg)-positive mothers. The other half are from horizontal transmission mainly through intrafamilial spread or injection using unsterilized needles. During the natural course of chronic HBV infection, spontaneous HBeAg/anti-HBe seroconversion occurs very rarely (2% annually) before 3 years of age. After 3 years of age, the HBeAg seroconversion rate increases gradually to 5% per year. Those with mothers who are hepatitis B carriers tend to clear HBeAg slower than those whose mothers are non-carriers. Transplacental HBeAg may cause T cell tolerance in infected children. Universal HBV immunization programmes have been effective in reducing the hepatitis B carrier rate more than 10-fold, and the incidence of hepatocellular carcinoma in children has also been decreased significantly. Hepatitis C virus infection occurs mainly in high-risk children, such as those who received blood products (blood diseases, malignancies, post-open heart surgery etc.), children of HCV-infected mothers, and in hyperendemic areas, from injection using unsterile needles. Mother-to-infant transmission occurs on average in 5% of infants of viraemic mothers. The maternal HCV-RNA titre is the most important factor determining the infectivity. Chronicity developed in 60-80% of HCV-infected children. Although transient or persistent elevation of aminotransferases occurs frequently in chronically HCV-infected children, liver histology showed minimal or mild changes only. The most prevalent genotype of HCV in children is Ib. Screening of the blood products for HCV antibody has markedly reduced the rate of HCV infection in children at risk. However, vaccine development is needed to prevent mother-to-infant transmission and other routes of infections.