A promoter polymorphism in the interferon alpha-2 gene is associated with the clinical presentation of hepatitis B.

Cytokine gene polymorphisms influence the severity of infectious diseases of viral and parasitic origin. Interferon alpha (IFN-alpha) is known to be involved in the defence against hepatitis B. The promoter of the IFN-alpha-2 gene was investigated for mutations in 344 hepatitis B virus (HBV)-infected Vietnamese patients and 293 uninfected Vietnamese. We found a deletion in the promoter, which was present significantly more frequently in HBV-infected patients than in control individuals; 20% of the healthy, whereas 35% of the HBV-infected cohort carries this deletion (P<0.001). Reporter gene assays showed that a construct with the deletion had a lower level of transcription in comparison to the wild type (P=0.011). These findings indicate that the deletion in the promoter of the IFN-alpha-2 gene reduces the transcription of this gene in vitro. This reduction could explain the individually different interferon levels in humans and could also be one cause of susceptibility to hepatitis B.

Serum cytokine profiles associated with clinical presentation in Vietnamese infected with hepatitis B virus.

BACKGROUND/OBJECTIVES: An ineffective cytokine response is thought to be one of the reasons for the failure to suppress hepatitis B virus (HBV) replication and to eliminate the virus. We investigated the serum levels of interleukin (IL)-6, IL-10, IL-12, and interferon (IFN)-gamma in HBV-infected Vietnamese patients to determine whether they were related to the outcome of HBV infection. STUDY DESIGN: Samples from a total of 154 HBV-infected patients with well-characterised clinical profiles and 56 healthy controls were assessed. RESULTS: Serum IL-6 levels, which were inversely correlated with transaminase levels, were highest in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and lowest in those with either asymptomatic (ASYM), acute or chronic HBV, and thus, represented the best marker of HBV-related clinical progression. Compared with the healthy control group, serum IL-12 was uniformly elevated in all HBV-infected patients apart from those with ASYM infections, implying no impairment of production of this cytokine in HBV-infected individuals. Serum IL-10 and IFN-gamma levels, however, were uniformly low and showed no association with clinical presentation. Cytokine profiles were not influenced by the presence of hepatitis B e antigen (HbeAg). CONCLUSIONS: Serum IL-6 and IL-12 but not IL-10 and IFN-gamma are associated with the clinical presentation in HBV-infected Vietnamese patients.

Mannose-binding lectin gene polymorphisms and hepatitis B virus infection in Vietnamese patients.

Mannose-binding lectin (MBL) is a constituent of the human innate immune system which may play an important role in combating a variety of infectious diseases. We investigated the distribution of MBL gene mutations in a Vietnamese population, using polymerase chain reaction and DNA sequence analysis, and sought associations with the outcome of hepatitis B virus (HBV) infection. For this purpose we used samples from a total of 123 patients with confirmed, well-defined HBV infections, representing a full spectrum of clinical presentation from acute to chronic to malignant states, as well as from 112 healthy controls. The only MBL gene mutation found in this population, that at codon 54 of exon 1, was present at an overall frequency of 0.12, with a trend towards a higher frequency in the HBV-infected group compared with controls (0.15 versus 0.08, P = 0.079). Within the HBV-infected group there was a non-significant trend towards higher viral loads in those with this mutation, accompanied by significantly higher serum transaminase levels in the same individuals. Segregation according to clinical presentation showed that the mutation was present at a significantly higher frequency in the group with acute hepatitis B (AHB) compared with the healthy control group (0.25 versus 0.08, P = 0.01), and was associated with higher serum transaminase levels. Our results indicate that a mutation of the MBL gene might influence the clinical outcome of HBV infection in Vietnamese patients.

Co-infection of human parvovirus B19 in Vietnamese patients with hepatitis B virus infection.

BACKGROUND/AIMS: Human parvovirus B19 (B19) has been identified in the serum of hepatitis B virus (HBV) infected patients. However, the effect of B19-infection on the course of HBV-associated liver disease has not previously been investigated. We examined the prevalence of B19-DNA in HBV-infected Vietnamese patients and analysed the association between co-infection and the clinical outcome of HBV-infection. METHODS: Serum samples from 399 HBV-infected patients and 64 healthy individuals were analysed for the presence of B19-DNA by PCR and DNA-sequencing. RESULTS: B19-DNA was detected in 99/463 (21.4%) individuals. The proportion of HBV-infected patients who were also co-infected with B19 was higher than the healthy controls (P<0.001). B19-DNA was detected more frequently in patients with HBV-associated hepatocellular carcinoma compared to patients with acute and chronic HBV, HBV-associated liver cirrhosis and healthy subjects (P<0.006). A positive correlation was also found between B19-DNA loads and both serum HBV-DNA loads and alanine aminotransferase (rho>0.250 and P<0.05). CONCLUSIONS: Our findings demonstrate that B19-infection is frequent in HBV-infected Vietnamese patients. Also, a significant correlation exists between HBV/B19 co-infection and a greater likelihood of progression to more severe hepatitis B-associated liver disease. Further studies are required to determine the role of B19-infection on HBV-associated pathogenesis.

Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam.

Eight genotypes (A-H) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in in vitro viral replication. In Asian patients, seven genotypes (A-G) were detected, with A, C, and D predominating. In European and African patients, only genotypes A, C, D, and G were identified. Genotype mixtures were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06). In Asian patients, the predominant genotype mixtures included A/C and C/D, compared to C/D in European and A/D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P < .0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P = .02). Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002). Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype (P = .019). Genotype mixtures were also associated with increased in vitro HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa, and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome.

Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus.

Earlier studies of both chronic hepatitis B and C virus (HBV and HCV) patients have shown a strong correlation between the soluble membrane Fas (sFas) and Fas protein expression on hepatocytes. The serum concentrations of sFas and soluble Fas ligand (sFasL) was examined in both healthy and HBV-infected Vietnamese patients to determine their relationship with the outcome of HBV infection. Patients with chronic rather than acute HBV had significantly higher amounts of sFas and sFasL, whilst the highest concentrations of both molecules were detected in those with malignant forms of HBV infection. sFas and sFasL concentrations tended to increase with a profile that paralleled the progression from asymptomatic to acute through chronic to malignant states, most markedly in the case of sFas. The sFas:sFasL ratio highlighted the relative predominance of sFas in those with acute and chronic HBV compared with asymptomatic or severe forms. In patients with hepatocellular carcinoma (HCC) a significant correlation was also observed between sFasL and alpha-feto protein (AFP) levels. The results indicate that sFas and to a lesser extent sFasL levels are to some degree associated with clinical progression in HBV infection.