Delta infection in chronic HBs Ag carriers in Tunisia: high prevalence in chronic asymptomatic HBs Ag carriers and in HBs Ag positive cirrhosis

The presence of hepatitis B virus DNA, delta antigen and anti-delta antibodies was examined in 159 Tunisian chronic HBs Ag carriers: 45 were asymptomatic and 114 suffered from cirrhosis. Serum hepatitis B virus DNA was detected in two (4.5%) asymptomatic HBs Ag carriers and in 11 (10%) HBs Ag positive cirrhosis patients. The prevalence of HDV infection determined by the presence of anti-delta was relatively high in asymptomatic HBs Ag carriers (33%) and in HBs Ag positive cirrhosis patients (21%). Active ongoing HDV infection, detected by serum HD Ag and anti-delta IgM, was shown in five patients with cirrhosis and active hepatitis B virus replication. We conclude that hepatitis delta virus may be endemic in Tunisia and does not always inhibit hepatitis B virus replication.     

Delta infection in asymptomatic carriers of hepatitis B surface antigen: low prevalence of delta activity and effective suppression of hepatitis B virus replication

We examined the prevalence of serum anti-delta antibody among 769 intravenous drug abusers in Taiwan. delta infection was found extremely common in the HBsAg-positive carriers with drug abuse, because 128 (85%) of 151 carriers were positive for anti-delta. However, most of antibody titers were low (less than 1:5,000). By molecular hybridization, delta RNA genomes were detectable in only five (4%) of 128 asymptomatic carriers positive for anti-delta. The results suggested that most of them had previous, instead of ongoing, delta infection. We also studied the serum markers reflecting hepatitis B virus replication in these carriers and a control group. Hepatitis B e antigen was positive in only 12 (10%) of 115 anti-delta positive carriers in contrast to 22 (23%) of 95 age- and sex-matched HBsAg-positive, anti-delta negative volunteers donating blood (p less than 0.025). Furthermore, in contrast to the close association between HBeAg and hepatitis B virus DNA generally present in HBsAg carriers (concordance in this series: 79%), among the 12 HBeAg-positive subjects of the delta infected group, only two, or 17%, had serum hepatitis B virus DNA (p less than 0.003). Such suppressing effects did not require a simultaneous presence of the delta agent, as shown by the lack of delta RNA genomes in the serum by sensitive assay. We conclude that although delta superinfection is common in the asymptomatic HBsAg carriers with intravenous drug abuse in the nonendemic area of Taiwan, continuous delta activities are uncommon in them. In addition, the previous delta infection probably exerts effective suppression on the hepatitis B virus replication in these HBsAg carriers.     

Delta agent infection in acute hepatitis and chronic HBsAg carriers with and without liver disease

Hepatitis B virus (HBV) is a major cause of chronic liver disease in southern Italy. In the same area superinfection with the delta agent is endemic. To assess the prevalence of delta infection in a large population of patients with acute and chronic HBV related liver disease and to look for differential features among delta infected and uninfected subjects sera from 592 consecutive HBsAg positive patients were tested for the delta/anti-delta system by RIA. In no case was delta Ag found in serum. The prevalence of anti-delta was low in acute hepatitis (6.6%) and in asymptomatic carriers (6.4%) but raised in chronic active hepatitis with or without cirrhosis (52.3%). A decrease in frequency of anti-delta was seen in inactive cirrhosis (38.8%) and in hepatocellular carcinoma (11.9%). A younger mean age of delta-infected subjects was observed in each type of chronic liver disease. Our data confirm that delta agent superinfection is definitely associated with severe chronic active liver disease. The difference in age between anti-delta positive and negative patients suggests that delta infection accelerates the natural history of HBV related liver disease.     

Epidemiology of hepatitis D virus (delta) infection in Yugoslavia

ABSTRACT— In 614 HBsAg-positive Yugoslavian patients, radioimmunoassay testing for anti-delta showed the presence of this antibody in serum in 11.2%. Of the patients, 213 belonged to a risk group (i.v. drug users, hemophiliacs, hemodialysed patients and patients with posttransfusion hepatitis); a significant number of these patients (63; 29.6%) were found to have anti-delta. A second group was composed of 401 HBsAg-positive patients from the general population (patients with acute hepatitis B, with fulminant hepatitis B and patients with chronic HBV infection); delta infection was found only in six (1.5%). Immunohistochemical methods failed to demonstrate the delta antigen in the livers of 73 patients with chronic HBV infection. Testing the liver of 36 patients with fulminant hepatitis B for delta antigen demonstrated this reactivity in only one (2.8%) liver sample. Delta antigen was also found in the liver of a female patient who underwent biopsy in 1972. The results of this study suggest the HDV is not endemic in Yugoslavia; however, it is frequently found in patients at risk of blood exposure, primarily i.v. drug users.     

Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis B virus carriers

Delta antigen is currently thought to reflect superinfection of the liver with a defective RNA virus (delta agent), requiring helper function from hepatitis B virus for its replication. To assess the influence of delta agent on hepatitis B virus replication in patients persistently infected with both viruses and showing chronic liver disease, we measured serum and liver hepatitis B virus DNA in HBsAg-positive chronic liver disease patients who were either positive or negative for delta antigen in the liver. Hepatitis B virus DNA was assayed in the serum of 21 patients with delta antigen-positive/HBsAg-positive chronic liver disease and in 21 patients with delta antigen-negative/HBsAg-positive chronic liver disease matched for HBeAg/anti-HBe status and underlying liver histology. HBcAg and delta antigen in liver was determined by immunofluorescence or immunoperoxidase staining. In delta antigen-positive/HBsAg-positive chronic liver disease, serum hepatitis B virus DNA was detected transiently in 4 of 21 cases (19%) and was present in these patients at low levels (trace to 2+). In contrast, 9 of 21 (43%) delta antigen-negative/HBsAg-positive chronic liver disease patients were serum hepatitis B virus DNA positive, and five of these had high serum hepatitis B virus DNA levels (3+ to 4+). Serum HBsAg and anti-HBc titers were significantly lower in delta antigen-positive cases and correlated with reduced amount of HBcAg in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of delta agent infection in chronic hepatitis B virus infection: a study in British carriers

Delta antigen (delta) is a transmissible agent requiring hepatitis B virus (HBV) for its replication. Antibody to delta (anti-delta) was present in nine of 71 (13%) British HBV carriers: six were intravenous drug abusers and two were haemophiliacs. Anti-delta was negative in 30 HBsAg positive homosexuals. Cirrhosis was common in patients with anti-delta and those with anti-delta positive cirrhosis were significantly younger than those with anti-delta negative cirrhosis. In British HBV carriers delta infection is associated with intravenous drug abuse and haemophilia and perhaps a more rapid progression of chronic liver disease.     

Infection with hepatitis delta virus in patients with fulminant hepatitis B and chronic HBsAg carriers in Bulgaria

To evaluate the prevalence and clinical significance of delta infection in a Bulgarian population, 105 HBsAG positive patients with chronic liver diseases, and 42 patients who had died of fulminant hepatitis B were studied. Delta antigen was detected by direct immunofluorescence in the liver of 9 patients with chronic HBV infection (8.6%), and in 3 patients with fulminant hepatitis (7.14%). All chronic HBsAg carriers with delta superinfection had chronic active hepatitis or active liver cirrhosis. They were predominantly anti-HBe (+) in the serum. The mean age and the mean values of serum transaminase did not differ in delta antigen positive and negative patients with chronic liver diseases. A history of parenteral manipulations directly before the hepatitis was present in patients with delta antigen positive fulminant hepatitis. These results indicate a relatively low incidence of delta infection in our population, but it is invariably associated with severe liver disease.     

Infection with the delta agent in children.

Serological evidence of infection with the hepatitis B virus associated delta agent (delta) was found in 34 of 270 Italian children with HBsAg-positive liver disease. In different histological forms of chronic HBsAg hepatitis the prevalence of delta infection increased in parallel with the activity of the disease and was maximal in children with cirrhosis. During two to seven years of follow up the hepatitis deteriorated in 38% of the 34 patients with delta infection and ameliorated only in 9%. By contrast the disease usually ran a mild course in the 236 delta-negative carriers of HBsAg, with remission in 55% of these children and deterioration in only 7%. The outcome of chronic hepatitis associated with delta infection was not influenced by treatment with steroids and azathioprine. Chronic delta infection in children is usually accompanied by serious liver disease, that has a tendency to progress and is unresponsive to conventional immunosuppressive treatment.     

Morbidity and mortality from chronic hepatitis B virus infection in family members of patients with malignant and nonmalignant hepatitis B virus-related chronic liver diseases.

Three-hundred forty-one HBsAg-positive family members of 152 patients with chronic hepatitis B virus infection (47 asymptomatic carriers, 59 with chronic hepatitis, 17 with cirrhosis and 29 with hepatocellular carcinoma) were prospectively studied to determine the morbidity and mortality from chronic hepatitis B virus infection in the family members of patients with malignant and nonmalignant hepatitis B virus-related chronic liver diseases. Most of the family members had no history of acute hepatitis, were asymptomatic and were unaware of their carrier status. However, 5.3% had stigmata of chronic liver disease, 6% had serum ALT levels that exceeded two times the upper limit of normal and 78% of those who had biopsies had chronic hepatitis with or without cirrhosis. During a follow-up period of 12 to 90 mo (median = 39 mo), 3% had symptoms of chronic liver disease; 24% had transient, recurrent or persistent elevation in serum ALT levels, 1.4% had cirrhosis and 1% had hepatocellular carcinoma. Neither hepatocellular carcinoma in the index patient nor a previous history of hepatocellular carcinoma in the family was associated with an increase in the morbidity and mortality from chronic hepatitis B virus infection in the HBsAg-positive family members.     

Delta agent infection: an unfavourable event in HBsAg positive chronic hepatitis

To investigate the clinical value of delta agent infection in HBsAg positive chronic hepatitis, we detected anti-delta antibody (anti-delta) in serum and delta antigen (delta-Ag) on sequential liver biopsies of nine patients with HBsAg-positive CPH and 45 patients with HBsAg-positive CAH without cirrhosis observed for at least 2 years. The initial group of patients with CAH was composed of 54 patients who were consecutively either left untreated or treated with 15 mg of prednisolone daily. Nine patients dropped out. Delta-Ag was searched by the direct immunofluorescence technique. HBsAg, anti-delta, HBeAg and anti-HBe were detected by RIA. All CPH patients were delta-Ag negative in the 1st liver biopsy and anti-delta negative in serum. Out of these nine patients, seven remained delta-Ag negative CPH throughout the observation and the remaining two became delta-Ag positive, anti-delta positive and developed CAH. The 73% of patients with CAH were delta-Ag positive on the 1st biopsy and anti-delta positive in serum. The patients in the delta-Ag positive group (24 were always delta-Ag positive and two became delta-Ag positive during the observation) more frequently than those in the delta-Ag negative group (10 were always delta-Ag negative and nine became delta-Ag negative during the study) showed deterioration or died (77 vs. 16%; P less than 0.001). Neither in the delta-Ag positive group nor in the delta-Ag negative group did prednisolone modify the course of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

DELTA ASSOCIATED HEPATITIS IN AUSTRALIA

Hepatitis B associated delta infection was found in Australian born narcotics users, patients with cirrhosis and hepatoma from Italy and Greece and in south east Asian immigrants. About 9% of patients with chronic hepatitis B were found to have intranuclear delta antigen in liver biopsies with immunofluorescence or anti-delta antibody in serum by radioimmunoassay. Delta may have been imported from southern Europe and Asia and a reservoir of delta infection may exist in narcotics users. Anti-delta was not found in hemophiliacs despite exposure to hepatitis B. Delta occurs in Australia and causes acute and particularly chronic hepatitis in addition to that caused by hepatitis B.     

Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.     

Nosocomial transmission of delta hepatitis

A previously asymptomatic carrier of hepatitis B virus receiving chronic hemodialysis developed acute delta hepatitis. The patient regularly received dialysis treatments on the same machine as a parenteral drug abuser with hepatitis B surface antigen (HBsAg)-positive chronic hepatitis whose serum was strongly positive for delta antibody. The drug abuser had a major bleeding episode that caused extensive environmental contamination 3 months before onset of illness in the index patient. No other patients receiving dialysis or staff members had evidence of delta infection. A surgeon previously infected with hepatitis B from the same parenteral drug abuser also had delta antibody. Testing for delta virus is indicated for both HBsAg-positive parenteral drug abusers and patients with hemophilia receiving chronic hemodialysis. All patients who are HBsAg- and delta-positive should receive dialysis separately from patients who are HBsAg-positive and delta-negative. Susceptible patients on dialysis and staff should receive hepatitis B vaccine to protect against both hepatitis B and delta virus infection.     

Long-term follow-up of anti-HBe-positive chronic active hepatitis B

Twenty-eight patients with chronic active hepatitis without cirrhosis who were positive for hepatitis B surface antigen and antibody to hepatitis B e antigen were followed for 1 to 15 years (mean 6.6 years) and underwent follow-up biopsy. At presentation, 12 of the 28 patients (43%) had hepatitis B virus DNA in serum, 10 (36%) had serologic evidence of hepatitis delta virus infection and 6 (21%) had no serologic markers of either hepatitis B virus replication or hepatitis delta virus infection. During follow-up, 15 (54%) patients developed active cirrhosis, including eight patients with hepatitis delta virus infection and five with hepatitis B virus DNA in serum. In seven (47%) of the 15 patients, cirrhosis developed within the first 2 years; all seven patients had bridging necrosis in the first liver biopsy, and five of these were infected with hepatitis delta virus. The remaining 13 (46%) patients did not develop cirrhosis during follow-up and showed either unchanged features of chronic active hepatitis (seven cases) or histologic improvement to chronic persistent hepatitis (five cases) or to normal liver (one case). In conclusion, the prognosis of anti-HBe-positive patients with chronic hepatitis B is poor, as 54% of the cases developed cirrhosis during a mean histologic follow-up period of 4.5 years, mainly in association with hepatitis delta virus infection or continuing hepatitis B virus replication.     

Infection with delta agent in Japan

It is estimated that approximately 70 to 80% of the world's HBsAg carriers live in Southeast Asia, but studies of delta infection in this area are still limited. We studied 323 HBsAg seropositive patients in Japan, and 4 (1.2%) of them were found to be positive for anti-delta antibody, with none positive for delta antigen. These four patients did not belong to the known high-risk groups for delta infection. One HBeAg positive female gave birth to a baby girl, and perinatal transmission of hepatitis B virus and delta was successfully blocked by a combination of hepatitis B immunoglobulin and vaccine. This study in the Tokyo-Chiba area showed delta infection, though low in frequency, among ordinary Japanese citizens. It has been reported that delta antigen is highly infectious to HBsAg carriers and that its infection will cause severe liver damage. Once introduced, it could become epidemic among non-drug users in a country where hepatitis B virus infection is endemic. At this moment, the only way of preventing such a disaster appears to be to reduce the number of chronic carriers by interruption of vertical transmission.     

Significance of IgM antibody to hepatitis B core antigen for the differential diagnosis of acute and chronic hepatitis B virus infection and for the evaluation of the inflammatory activity of type B chronic liver diseases

IgM antibody to hepatitis B core antigen (anti-HBc) was assayed using a commercial kit in acute and chronic hepatitis B virus (HBV) infection and evaluated for its diagnostic and clinical significance. IgM anti-HBc was positive in all of 21 cases with type B acute hepatitis in the acute phase, and was also detected in 5 of 20 cases with type B chronic persistent hepatitis, in 4 of 20 patients with type B chronic active hepatitis and in one of 10 with type B liver cirrhosis. The absence of this marker was noted in all of 20 asymptomatic hepatitis B surface antigen (HBsAg) carriers and in 50 with HBsAg-negative patients with liver disease and in 200 healthy blood donors. The cut-off index of IgM anti-HBc was greater than 2.0 in all serum samples obtained in the acute phase of type B acute hepatitis, but was below 2.0 in type B chronic liver disease. A close relationship was found between the presence of IgM anti-HBc and the degree of inflammatory activity in patients with HBsAg-positive chronic liver disease. These data show that examination of IgM anti-HBc is useful in distingushing type B acute hepatitis from type B chronic liver disease, and also in evaluating the severity of disease in type B chronic liver disease.     

Epidemiology of Delta Agent Infection in Arabia: Geographical Distribution and Prevalence of Anti-Delta

The epidemiology of infection with the recently discovered delta (delta) agent was assessed in Saudi Arabia from the prevalence of antibody to delta (anti-delta) in 488 HBsAg-seropositive subjects from various regions of the country. In the Riyadh area, anti-delta was prevalent in 22.2% of chronic hepatitis B patients compared to 7.9% and 6.7% in active hepatitis B patients and HBsAg carriers, respectively. Anti-delta was also prevalent in HBsAg carriers from Al-Hafouf (5.3%) and Najran (9.6%), but no anti-delta was detected in 40 HBsAg-positive polytransfused thalassemics and in 145 HBsAg carriers from Jaizan and Khaiber. It seems that delta infection is present in only certain regions of Saudi Arabia, and infection is possibly transmitted parenterally in these populations.     

Hepatitis delta virus infection in southern Taiwan

To determine the prevalence of hepatitis delta virus (HDV) infection in Southern Taiwan in comparison to that of Northern Taiwan, a consecutive series of 389 HBsAg-positive patients were tested for serum antibody to HDV (anti-HD) by radioimmunoassay. The anti-HD was positive in 2/122 (1.6%) asymptomatic "healthy" carriers, 1/61 (1.6%) blood donors, 1/24 (4.2%) patients with acute type B hepatitis, 4/25 (16%) carriers with superimposed acute hepatitis, 5/53 (9.4%) patients with chronic hepatitis, 3/42 (7.1%) patients with liver cirrhosis and 1/62 (1.6%) patients with hepatocellular carcinoma. Our findings confirm that the prevalence of HDV infection is low in asymptomatic carriers, acute type B hepatitis and hepatocellular carcinoma, but significantly higher in patients with chronic active liver disease. No significant difference in the prevalence of HDV infection between Southern and Northern Taiwan was observed.     

Delta hepatitis in Lebanon. Prevalence studies and a report on six siblings with chronic delta-positive active hepatitis

The prevalence of delta infection in Lebanon is reported for the first time. Delta antigen and antibody were screened for in serum of 43 patients consecutively seen in hospital, 22 with acute hepatitis B (anti-HBc IgM-positive), and 21 with histological evidence of chronic active hepatitis, 6 of whom were brothers in a sibship of eleven. Twenty asymptomatic HBsAg carriers without clinical or biochemical evidence of liver disease were similarly studied. None of the asymptomatic carriers or acute hepatitis B patients had markers of delta infection. In contrast, delta antibody in high titre (greater than 1:5000) was found in 12 (57%) of the patients with chronic active hepatitis, including all six brothers. Five sisters in the sibship were anti-HBs-positive without evidence of liver disease, suggesting a horizontal mode of transmission of the delta virus, as a superinfection on a hepatitis B carrier state. Excluding the sibship, delta infection was present in 6 of 15 (40%) chronic active hepatitis patients. This prevalence is similar to other Middle Eastern countries. Delta infection was associated with severe liver disease.