Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting

ABSTRACT Aims: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). Methods: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100 mg daily), adefovir (ADV, 10 mg daily), telbivudine (LDT, 600 mg daily), entecavir (ETV, 0.5 mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. Results: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p < 0.001, Hazard Ratio (HR) = 2.203), elevated alanine aminotransferase (ALT) levels (p < 0.001, HR = 2.049), and non-vertical transmission (p = 0.006, HR = 1.656) were predictors of HBeAg seroconversion. Conclusion: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.

Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting.

AIMS: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). METHODS: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100mg daily), adefovir (ADV, 10mg daily), telbivudine (LDT, 600mg daily), entecavir (ETV, 0.5mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. RESULTS: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p<0.001, Hazard Ratio (HR)=2.203), elevated alanine aminotransferase (ALT) levels (p<0.001, HR=2.049), and non-vertical transmission (p=0.006, HR=1.656) were predictors of HBeAg seroconversion. CONCLUSION: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.

Association of PRKAA1 gene polymorphisms with chronic hepatitis B virus infection in Chinese Han population

ABSTRACT Objective: Studies have indicated that AMPK play critical roles in the regulation of innate immunity and inflammatory responses. However, the role of the polymorphisms of PRKAA1 gene in immune-response to infectious organisms remains unknown. To evaluate the potential role of PRKAA1/AMPKα1 in the immune-response to HBV, we conducted this case-control study. Methods: We recruited 276 patients (145 men and 131 women; average age, 51.6 years) with chronic HBV infection (CHB) and 303 healthy controls (166 men and 137 women; average age, 54.2 years). All the subjects were unrelated individuals of Chinese Han Population. Three SNPs of PRKAA1gene were tested. Results: Rs1002424 polymorphism showed significant difference in the allele frequencies, but no difference in the genotype frequencies (allele: p = 0.039411, OR95%CI = 0.783479 [0.621067-0.988362]; genotype: p = 0.104758); rs13361707 polymorphism showed significance in allele analysis, but not in genotype analysis (allele: p = 0.034749, OR95%CI = 1.284303 [1.017958-1.620335]; genotype: p = 0.098027); rs3792822 polymorphism was demonstrated to have significant differences in both genotype and allele frequencies between cases and controls (allele: p = 0.029286, OR95%CI= 0.741519 [0.566439-0.970716]; genotype: p = 0.034560). The haplotype results showed that CTG and TCA in the rs13361707-rs1002424-rs3792822 block were significantly associated with the happening of HBV (CTG: p = 0.036854, OR95%CI = 1.281 [1.015-1.617]; p = 0.030841, OR95%CI = 0.743 [0.568-0.973]). Conclusion: These findings suggest that PRKAA1 polymorphisms may contribute to the susceptibility of chronic HBV infection in Chinese Han origin.

Association of PRKAA1 gene polymorphisms with chronic hepatitis B virus infection in Chinese Han population.

OBJECTIVE: Studies have indicated that AMPK play critical roles in the regulation of innate immunity and inflammatory responses. However, the role of the polymorphisms of PRKAA1 gene in immune-response to infectious organisms remains unknown. To evaluate the potential role of PRKAA1/AMPKα1 in the immune-response to HBV, we conducted this case-control study. METHODS: We recruited 276 patients (145 men and 131 women; average age, 51.6 years) with chronic HBV infection (CHB) and 303 healthy controls (166 men and 137 women; average age, 54.2 years). All the subjects were unrelated individuals of Chinese Han Population. Three SNPs of PRKAA1gene were tested. RESULTS: Rs1002424 polymorphism showed significant difference in the allele frequencies, but no difference in the genotype frequencies (allele: p=0.039411, OR95%CI=0.783479 [0.621067-0.988362]; genotype: p=0.104758); rs13361707 polymorphism showed significance in allele analysis, but not in genotype analysis (allele: p=0.034749, OR95%CI=1.284303 [1.017958-1.620335]; genotype: p=0.098027); rs3792822 polymorphism was demonstrated to have significant differences in both genotype and allele frequencies between cases and controls (allele: p=0.029286, OR95%CI= 0.741519 [0.566439-0.970716]; genotype: p=0.034560). The haplotype results showed that CTG and TCA in the rs13361707-rs1002424-rs3792822 block were significantly associated with the happening of HBV (CTG: p=0.036854, OR95%CI=1.281 [1.015-1.617]; p=0.030841, OR95%CI=0.743 [0.568-0.973]). CONCLUSION: These findings suggest that PRKAA1 polymorphisms may contribute to the susceptibility of chronic HBV infection in Chinese Han origin.

-173G/C polymorphism in the promoter of MIF is associated with hepatitis B virus infection in a Chinese Han population.

In addition to the host immune response, genetic and environmental factors play crucial roles in the manifestation of hepatitis B virus (HBV) infection. The macrophage migration inhibitory factor (MIF) -173G/C polymorphism (rs755622), located in the promoter region of MIF, may play integral roles in diverse processes, including the immune response. Thus, the MIF -173G/C polymorphism may influence the immune response to HBV during natural infection. We investigated whether the MIF -173G/C polymorphism was associated with susceptibility to HBV infection in a Chinese Han population. A total of 596 HBV infection cases and 612 age-matched controls were recruited for the study. Genotyping of the MIF -173G/C polymorphism was performed using the allele-specific polymerase chain reaction method. The frequencies of the alleles and genotypes in patients and controls were compared using the χ(2) test. Carriers of the variant C allele in MIF -173 G/C were at significantly higher risk of HBV infection than carriers of the wild-type allele (P = 0.032, odds ratio = 0.799, 95% confidence interval = 0.651-0.981). However, there was no significant difference in the distribution of MIF -173G/C genotypes between case and control groups in either population (P = 0.096, degrees of freedom = 2). Our findings indicate that the G to C base change in MIF -173 G/C confers an increased risk of development of HBV infection by altering the expression of MIF in our Chinese Han population.

Relationships between transient elastography values and liver fibrosis in chronic liver disease patients with normal or mildly abnormal aminotransferase levels.

This study aimed to evaluate relationships between transient elastography values and liver fibrosis in chronic liver disease patients with normal or mildly abnormal aminotransferase levels. Fifty-six patients were enrolled in the study. Transient elastography and liver biopsy were performed on the same day, and the fibrosis was staged based on the Scheuer scoring system. Liver stiffness was measured to assessed liver fibrosis using transient elastography. The transient elastography values of 12 patients with chronic hepatitis B were studied before and 6 months after antiviral treatment. The sensitivity and specificity for 10.88 kPa in S3 were 80 and 87.8%, and for 19.4 kPa in S4, were 100 and 90.7%, respectively. In univariate analysis, liver stiffness strongly correlated with the fibrosis stage (r = 0.70, P < 0.5), moderately correlated with the aminotransferases (r = 0.398, P < 0.05), and poorly correlated with the degree of necroinflammatory activity (r = 0.19, P < 0.5). In multivariate regression, liver stiffness correlated only with the fibrosis stage (P < 0.05). Pre- and post-treatment viral loads were not significantly different [(4.81 ± 0.15) x 10(6) vs (7.62 ± 0. 16) x 10(3), P > 0.05]. Pre- and post-treatment LS measurements were not correlated with viral load (P > 0.05). Pre- and post-treatment LS measurements were not significantly different (P > 0.02). In conclusion, transient elastography values correlated with the stage of cirrhosis, alanine aminotransferase levels, and antiviral treatment in patients with chronic hepatitis B and did not correlate with viral loads.

Serum N-glycomic markers in combination with panels improves the diagnosis of chronic hepatitis B.

AIM: The present study aimed to evaluate the changes in the serum N-glycome profiles in chronic hepatitis B (CHB) patients and to assess the role of N-glycome-derived markers in the noninvasive diagnosis of liver fibrosis. MATERIALS AND METHODS: After liver biopsy for pathological grading and staging, 128 CHB patients underwent serum N-glycomic analysis using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE) and sensitive markers were screened. RESULTS: Peaks 1, 2, 8 and 10 in the N-glycome profiles could, to some extents, distinguish liver fibrosis at different stages. In addition, the N-glycome-derived marker log(peak2/peak8) possessed the highest diagnostic accuracy. The areas under the receiver operating characteristic (AUROCs) curves of the log(peak2/peak8) were 0.675, 0.736 and 0.754 in the diagnosis of significant fibrosis, advanced fibrosis and early cirrhosis, respectively. In combination with some marker panels (SLFG, S index, Fibrometer, Hui, Forns, APRI and Hepascore), it showed the best diagnostic potency in distinguishing significant fibrosis (SLFG + log[peak2/peak8], AUROC = 0.813) from advanced fibrosis (SLFG + log[peak2/peak8], AUROC = 0.899) and a better diagnostic potency in the identification of early cirrhosis (S index + log[peak2/peak8], AUROC = 0.903, lower than Hui model [AUROC = 0.927]) in the validation cohort. CONCLUSIONS: N-glycomic changes are present in the serum of CHB patients with liver fibrosis, and N-glycan profiling is a noninvasive and effective tool to assess the liver fibrosis, especially in combination with serum marker panels.

What is the reason of elevated alanine aminotransferase level in HBeAg negative patients with low viremia: NAFLD or chronic hepatitis?

BACKGROUND AND STUDY AIMS: Increased alanine aminotransferase (ALT) levels with negative hepatitis B virus (HBV) DNA by hybridization is a common problem in Turkey where is a mild endemic region. We aimed to evaluate the causes of elevated ALT levels in patients who are negative for hepatitis B e antigen (HBeAg) and HBV DNA (by hybridization) for at least 6 months. PATIENTS-METHODS: Forty-nine patients were enrolled in this study. Histological changes [histological activity index (HAI), and the extent of fibrosis] were assessed according to the Knodell scoring system and steatosis were graded by Brunt's classification for NAFLD in all patients. RESULTS: A mean age of the patients was 34.9 +/- 12.1 years (16-70). 43 (87.8%) of them were male. Mean ALT level was 95 +/- 39.7 IU/L (50- 258). Hyperglycemia (>100 mg/dL) and hyperlipidemia were found in 12 and 24 patients, respectively. Hepatic steatosis (7 patients grade 1; 5 patients grade 2; and 7 patients grade 3), ground-glass hepatocyte, chronic hepatitis, and Wilson disease were found in liver biopsy in 38.8%, 32.6%, 26.6%, 2%, respectively. Mean HAI was 6.5 +/- 3.6 (4-12) in chronic hepatitis. Seven patients (53.9%) were in stage 1 and 2 while 6 patients (46.1%) were in stage 3 and 4. CONCLUSIONS: Nonalcoholic fatty liver disease is the most common cause of elevated ALT levels in HBeAg negative/HBV DNA negative patients. Chronic hepatitis B was found in 26.6% of these patients.

[Long-term use of lamivudine for treating chronic hepatitis B in the State of Mato Grosso]. / Lamivudina por tempo prolongado no tratamento da hepatite B crônica no estado de Mato Grosso.

To assess the results from lamivudine treatment (100 mg or 150 mg) for chronic hepatitis B, 34 patients were followed at a clinic in Cuiabá, Mato Grosso, Central Brazil. Among them, 21 (62%) had liver cirrhosis and 24 (70%) were HBeAg-positive. The viral genotype was determined for 18 patients, among whom genotype A was the most prevalent (12). The median follow-up was 27 months (range from 7 to 64 months). Among the total, 23 (67%) presented a biochemical response after 2 to 24 months of treatment. Among the 24 HBeAg-positive subjects, 13 (54%) became HBeAg-negative during the follow-up. Among the anti-HBe-positive patients, 70% obtained normalization of aminotransferase levels. Fourteen (41%) did not present any initial biochemical or serological response or presented breakthrough. The L180M and M204V mutations were found in six of the non-responders. Four patients died after at least 21 months of lamivudine and three patients with liver cirrhosis developed liver cancer after 24 months. From the third year onwards, complications such as digestive system hemorrhage or liver cancer started to emerge. The present findings suggest that an early response to lamivudine treatment may be associated with better control over chronic hepatitis B.

Lamivudina por tempo prolongado no tratamento da hepatite B crônica no estado de Mato Grosso / Long-term use of lamivudine for treating chronic hepatitis B in the State of Mato Grosso

Para avaliar resultados do tratamento da hepatite B crônica com lamivudina, 100mg ou 150mg diários, foram acompanhados 34 pacientes em um serviço em Cuiabá, Mato Grosso. Entre os 34, 21 (62 por cento), eram cirróticos e 24 (70 por cento) HBeAg positivos. Genótipo viral foi determinado em 18, sendo predominante o genótipo A (12). O acompanhamento teve mediana de 27 meses (7 a 64). Do total, 23 (67 por cento) apresentaram resposta bioquímica entre dois e 24 meses de tratamento. Dos 24 pacientes com positividade para o HBeAg, 13 (54 por cento) apresentaram negativação do HBeAg durante o acompanhamento. Entre os anti-HBe positivos, 70 por cento tiveram normalização das aminotransferases. Quatorze (41 por cento) não apresentaram resposta bioquímica ou sorológica de início ou apresentaram breakthrough. Em seis dos que não responderam, foram encontradas as mutações L180M e M204V. Quatro pacientes faleceram após pelo menos 21 meses de lamivudina e três cirróticos desenvolveram hepatocarcinoma após 24 meses. A partir do terceiro ano surgiram complicações, como hepatocarcinoma ou hemorragia digestiva. Os presentes achados sugerem que resposta precoce ao tratamento com lamivudina pode estar associada a um melhor controle da hepatite B crônica.

To assess the results from lamivudine treatment (100 mg or 150 mg) for chronic hepatitis B, 34 patients were followed at a clinic in Cuiabá, Mato Grosso, Central Brazil. Among them, 21 (62 percent) had liver cirrhosis and 24 (70 percent) were HBeAg-positive. The viral genotype was determined for 18 patients, among whom genotype A was the most prevalent (12). The median follow-up was 27 months (range from 7 to 64 months). Among the total, 23 (67 percent) presented a biochemical response after 2 to 24 months of treatment. Among the 24 HBeAg-positive subjects, 13 (54 percent) became HBeAg-negative during the follow-up. Among the anti-HBe-positive patients, 70 percent obtained normalization of aminotransferase levels. Fourteen (41 percent) did not present any initial biochemical or serological response or presented breakthrough. The L180M and M204V mutations were found in six of the non-responders. Four patients died after at least 21 months of lamivudine and three patients with liver cirrhosis developed liver cancer after 24 months. From the third year onwards, complications such as digestive system hemorrhage or liver cancer started to emerge. The present findings suggest that an early response to lamivudine treatment may be associated with better control over chronic hepatitis B.

Interferon treatment for chronic hepatitis B: enhanced response in children 5 years old or younger.

OBJECTIVE: To test the hypothesis that there is an improved response to interferon in children with chronic hepatitis B (HBV) who are < or =5 years of age. STUDY DESIGN: Retrospective chart review of 22 consecutive children with chronic HBV (ages 17 months to 17 years; median, 83.9 months; 14 male, 8 female) treated with interferon-alpha2b. RESULTS: Ten patients (48%) responded to treatment [HBeAg (-), Anti-HBe (+), HBV DNA (-), HBsAg (+) and normal alanine aminotransferase/aspartate aminotransferase (ALT/AST) at 6 months after treatment], and 5 seroconverted HBsAg [above plus HBsAg negative and anti-HBs (+)]. Seven of 9 patients (78%) < or =5 years of age responded (5 cleared HBsAg). Three of 13 patients (23%) >5 years of age responded. Patient age at treatment was significantly lower in responders (63 +/- 70 months) versus nonresponders (104 +/- 55 months, P =.005). AST, ALT, and HBV DNA at the start of treatment were not different between responders and nonresponders or between patients < or =5 and >5 years old. CONCLUSIONS: Interferon treatment may be more effective in younger children with chronic hepatitis B.

Efficacy and tolerability of long-term therapy using high lamivudine doses for the treatment of chronic hepatitis B.

PURPOSE: A long-term follow-up study was carried out to evaluate the tolerability and efficacy of long-term therapy (1 to 3 years) with high doses (150 or 300 mg daily) of lamivudine for chronic hepatitis B. METHODS: Thirty-two patients were studied, including those who were seronegative for hepatitis B e antigen (HBeAg), as well as those with decompensated liver cirrhosis. Viral DNA clearance was monitored by using end-point dilution polymerase chain reaction (PCR), a highly sensitive method. Hepatitis B virus (HBV) polymerase gene mutations associated with resistance were determined by sequencing. RESULTS: Response to lamivudine in the sixth month was observed in 19/32 (59.4%) patients. With one exception, viral DNA results observed at this time were maintained. The YMDD mutation was detected in 12 nonresponder patients (9 YVDD, 2 YIDD, and 1 mixed population Y(V/I)DD), generally associated with the L528M mutation. Re-takeover by the wild type was observed 6 to 18 months after lamivudine withdrawal. Lamivudine response rates in noncirrhotic and cirrhotic patients were 9/18 (50%) and 10/14 (71.4%), respectively. HBeAg to anti-HBe seroconversion was found after different periods in all responder patients. Hepatitis B surface antigen (HBsAg) clearance and anti-HBs seroconversion were occasionally found. CONCLUSIONS: In nonresponder patients, resistant mutants appeared up to the second year of lamivudine therapy. In spite of the presence of resistant mutants, maintenance of therapy was usually associated with a lower viral load. In responder patients, maintenance of therapy was associated with continued absence of detectable HBV DNA in serum, as monitored by highly sensitive methods. No significant side effects caused by lamivudine were observed in our patients, even in those with liver cirrhosis.

Efficacy of ribavirin in patients with chronic hepatitis B.

This study aimed to evaluate the efficacy and safety of a 6-month course of ribavirin (Rb) (1200 mg/day) in the treatment of chronic hepatitis B (CHB). Sixty patients with CHB were randomly assigned in a double-blind placebo (Pl) controlled study; 30 patients received oral Rb (1200 mg/day) and 30 received Pl for 24 weeks. Patients were hepatitis B surface antigen (HBsAg); hepatitis B envelope antigen (HBeAg); and hepatitis B virus (HBV)-DNA-positive, with alanine aminotransferase (ALT) levels 1.5 times higher than normal values. Clinical evaluations and laboratory tests were carried out at regular intervals; tests included total blood cell count, liver function tests, and HBV serum markers. Baseline and control liver biopsies were carried out. HBeAg seroconversion occurred in 50.0% of the patients in the Rb group (vs 6.6% in the Pl group; P = 0.00019); HBV DNA negativization occurred in 33.3% in the Rb group (vs 6.6% in the Pl group; P = 0.009); and improvement in the necroinflammatory index occurred in 53.3% in the Rb group (vs 23.3% in the Pl group; P = 0.02). The drug was well tolerated; the most important side effect in the Rb group was hemoglobin reduction, which was reversible once the treatment was stopped. Ribavirin was an effective treatment, demonstrated by decreased ALT levels, alleviation of histological damage, seroconversion of HBeAg, and HBV-DNA negativization; Rb may be an alternative agent in the treatment of CHB, without significant side effects.