Unexpected low prevalence of delta antibodies in the east Amazon region and S?o Paulo: evidence for regional differences in the epidemiology of delta hepatitis virus within Brazil

Antibodies (anti-HD) to hepatitis delta virus (HDV) were tested by radioimmunoassay in 207 human serum samples from the eastern Amazon (states of Pará and Amapá) and S?o Paulo, Brazil. 42 Amazon HBsAg asymptomatic carriers were negative for anti-HD. 84 S?o Paulo HBsAg asymptomatic carriers were also negative. Among the 81 HBsAg patients from S?o Paulo with different liver diseases, only one had anti-HD. Liver biopsy of this chronic active hepatitis case was positive for HBsAg, HBcAg and HDAg in liver, by an immunoperoxidase technique. The low prevalence of HDV infections in S?o Paulo and eastern Amazon was unexpected and contrasts with the recent reports of high prevalence in the western Amazon region. Such regional differences emphasize the need for extensive and precise worldwide epidemiological studies of HDV.     

392例HBsAg阳性急慢性肝炎和携带者血清δ系统的研究

本文应用国产丁型肝炎病毒(HDV)酶联免疫试剂对392份HBsAg阳性肝炎和携带者血清进行了抗-HD、抗-HDIgM和HDAg测定,HDV总感染率为10.7％(42/392)。其中以重型肝炎组HDV标志检出率最高,达27.8％,然后依次为慢性肝病(15.5％)和急性乙肝(5.3％),HBsAg阳性携带者无1例阳性。本研究资料提示HDV感染对HBV感染在加重肝损害、促进肝脏炎症进展及慢性化方面均起十分重要作用。HDV标志与HDV RNA的测定亦有较高的符合率(96.9％)。     

Epidemiology and clinical outcome of hepatitis D virus infection in Turkey

The prevalence, the epidemiology, the clinical and biochemical characteristics of hepatitis delta virus (HDV) infection were studied in patients with HBsAg-positive acute hepatitis, in those with chronic liver disease, and in apparently healthy carriers in Turkey.Fifty-eight of the 242 carriers of HBsAg (23.9%) and 31 of the 237 (13.1%) patients with acute HBsAg-positive hepatitis had serological evidence of HDV infection. Eleven of these individuals were HBsAg carriers with acute HDV superinfection. The prevalence of HDV infection was significantly (p < 0.001) higher in patients with chronic liver disease (54/165; 32.7%) than in asymptomatic carriers of HBsAg (4/77; 5.2%). The highest prevalence (26/57; 45.6%) of HDV infection was found in patients at high risk of acquiring hepatitis virus infection (health care workers, hemodialysis patients, polytransfused patients) with chronic liver disease.Whereas the frequency of severe or fulminant hepatitis was similar in HBV infected patients (7.8%) and in HBV/HDV coinfected individuals (10%), the frequency of biphasic hepatitis was significantly (p < 0.005) higher in the latter patients (30%) than in those with classical hepatitis B (7.8%). Chronic evolution of the disease was observed in 3.9% of the patients with classical hepatitis B and in 5% of those who had evidence of simultaneous HBV/HDV infection. The 10 carriers of HBsAg who survived the acute HDV superinfection developed chronic delta hepatitis.These findings indicate that HDV is endemic in Turkey and that its prevalence is highest among chronic HBsAg-positive hepatitis patients, implicating HDV as a major cause of liver disease among urban Turkis.Corresponding author.     

河南省人群丁型肝炎病毒感染的血清流行病学调查研究

为了了解河南省丁型肝炎病毒的人群感染情况，从１９９１－１９９３年对河南省十三个地区１１８２例ＨＢｓＡｇ阳性的各型乙肝病人及无症状ＨＢｓＡｇ携带者血清标本进行ＨＤＡｇ、抗ＨＤＶ和ＩｇＭ－抗－ＨＤＶ三项标志检测。结果表明，河南省人群ＨＤＡｇ、抗－ＨＤＶ、ＩｇＭ－抗－ＨＤＶ的总感染率分别为３．０％、３．５％、３．５％、８．１％。     

High HBsAg and anti-delta carrier rate among asymptomatic Africans living on the campus of the University of Niamey, Niger

In 1984 and 1985, a non-random survey was conducted among healthy Africans living on the campus of the University of Niamey, Niger. Of 238 asymptomatic subjects, 17.6% carried hepatitis B surface antigen (HBsAg) in their serum, while 50.8% demonstrated protective anti-HBs antibodies. Antibodies to delta virus were detected in 29.3% of HBsAg-positive sera. This suggests that hepatitis B virus (HBV) and hepatitis delta virus (HDV) are common in Niger, and the factors that increase the likelihood of HBV transmission may also enhance the risk of HDV transmission.     

Delta virus infection in Egypt.

The present study was carried out on 124 serum samples of acute hepatitis B, 51 with chronic HBV infection, and 41 chronic HBsAg carriers. Sera were tested by ELISA for HBV markers and anti-delta (anti-HDV). Delta infection (anti-HDV) in acute HB was found to be 16.9% (21 out of 124), 23.5% in chronic HB cases (12 out of 51), and 21.9% among chronic HBsAg carriers (9 out of 41). Out of the twelve delta positive in chronic HB patients, ten (83%) were suffering from CAH (chronic active hepatitis) denoting a possible role of delta infection in deteriorating the course of the disease. A competitive inhibition of HBV replication by coexistent delta infection was demonstrated in the present study. This was reflected on anti-HBc IgM in the acute cases and on HBeAg in chronic HB cases. Anti-HBc IgM was 71.42% (15 out of 21) in delta positive acute HB patients versus 92.23% (95 out of 103) in delta negative acute HB patients. On the other hand, HBeAg percentage was 8.33% (1 out of 12) and 46.15% (18 out of 39) in delta and non-delta chronic HB patients respectively. The difference in both anti-HBc IgM and HBeAg as regards delta positive and negative patients was found to be statistically significant. Out of the twelve chronic HB cases with delta infection, four cases were negative for HBsAg (33.33%). This observation might be attributed to the clearance effect of hepatitis D virus (HDV) on HBsAg (Ischimura et al., 1988) or due to suppressing effect resulting in low undetectable HBsAg level in serum, (Sherlock, 1989). From the present study it may be concluded that delta infection is endemic in Egypt (its incidence ranged from 16.94% in acute HB to 23.53% in chronic HB infection), delta infection possibly also worsens the outcome of chronic HB patients. Delta infection may exert a competitive inhibitory effect on HBV replication.     

Search for hepatitis delta virus (HDV) infection in hepatitis C patients in north-eastern Poland. Comparison with anti-HDV prevalence in chronic hepatitis B

Hepatitis C virus and hepatitis D virus have been shown to suppress HBsAg synthesis. Thus it is possible that HDV infection occurs despite the lack of detectable HBsAg. The aim of our study was to (a) determine the prevalence of HDV infection in patients with chronic hepatitis C (b) compare it with the prevalence of HDV infection in HBsAg positive patients with hepatitis B. The study group consisted of 51 chronic hepatitis C patients, 30 HIV infected drug addicts (27 of them were also positive for anti-HCV) and 102 hepatitis B patients. The participants were tested for anti-HDV, anti-HCV and HBsAg. All anti-HCV positive patients were negative for anti-HDV. Four individuals with anti-HDV belonged to hepatitis B group and constituted 3.9% of all HBsAg positive subjects. We conclude that (a) there is currently no evidence of HDV infection among HCV infected patients in our region (b) hepatitis delta infection is rare in north-eastern Poland.     

Epidemiology and long-term consequences of hepatitis delta virus infection in the Yucpa Indians of Venezuela.

To define better the epidemiology and clinical impact of hepatitis delta virus (HDV) infection among hepatitis B virus (HBV) carriers in less developed countries, the authors prospectively studied a cohort of 216 Yucpa Indian HBV carriers in Venezuela. HBV carriers were followed regularly between 1983 and 1988 by physical examination, laboratory testing for liver enzymes and HBV and HDV markers, and epidemiologic history. Among the cohort, 74 (34%) were initially positive for HDV infection, and 35 additional persons became infected during the study. Risk factors for new HDV infection included living in southern Yucpa villages; being young adults (15-19 years) or young children (1-9 years), and living in a household with a person with acute HDV infection. Persons with HDV infection were at high risk of developing chronic liver disease; 56% of HDV-infected persons had moderate-to-severe chronic liver disease at the end of the study compared with none of the HBV carriers without HDV infection. Mortality rates were 6.9% and 8.8% per year, respectively, among initially HDV-positive HBV carriers and those with new HDV infection, because of rapidly progressive chronic liver disease and fulminant hepatitis; mortality was significantly lower in HBV carriers without HDV infection and in non-HBV carriers. HDV superinfection is a devastating disease in HBV carriers in tropical South America. Prevention of HBV infection with hepatitis B vaccine is the best available tool to reduce the impact of this problem.     

Clinical significance of serum HBeAg and HBV-DNA-specific values of virus replication in chronic hepatitis-B virus infection.

The prevalence of serum HBV-DNA and that of HBeAg was evaluated in 44 subjects (27 males and 17 females) aged between 3 and 59 years. They were divided in two groups: (A) chronic asymptomatic HBsAg carriers; and (B) chronic HBsAg carriers with a history of HBV infection. The patients had been chronic HBV carriers between 8 months and 15 years. All underwent clinical and biochemical evaluation. The serological markers of HBV infection were tested using ABBOTT assay kits. The serum HBV-DNA was quantified using a hemiluminiscence molecular hybridization assay (Digene-Murex). HBV-DNA+ were 13 patients (29.55 +/- 6.88%). The highest level of viral replication (up to 50%) was measured in the patients aged from 3 to 29 years while in the others a 3 to 4-fold decrease of the viral replication was detected. HBV-DNA+ were 8 (23.53 +/- 6.39%) of the chronic asymptomatic hepatitis B carriers and 5 (50.00 +/- 7.5%) of the chronic HBV carriers with former acute hepatitis B infection. Similar results were obtained for the other index of viral replication--HBeAg/anti-HBe. Eight (23.53 +/- 6.39%) patients from group I and 4 (40.00 +/- 7.38%) patients from group II were HBeAg+ while anti-HBe+ were 26 (76.47 +/- 6.39%) and 6 (60.00 +/- 7.38%) patients from group I and II, respectively, i.e., about a quarter of the chronic asymptomatic HBsAg carriers and half of the chronic HBV carriers that had had an acute hepatitis B virus infection had HBV replication in their bodies. HBeAg+ patients had high levels of serum HBV-DNA (625.70-3328.00 pg/ml) which indicated extremely intensive viral replication. The presence of HBeAg and especially of HBV-DNA as markers of viral replication in chronic asymptomatic HBsAg carriers and chronic HBsAg carriers with a prior acute hepatitis B virus infection provide important information for the clinical decisions.     

丁型肝炎病毒感染的血清流行病学观察

1987年4月至1988年10月间,本文应用酶联吸附法(EIA)对石家庄地区Ml例乙型肝炎病毒感染者进行了抗-HD的检测,共发现35例阳性,阳性率12.92%,其中男性阳性率14.06%(27/102),女性为10.13%(8/79),男女间差异无统计学意义(P>0.05),提示石家庄地区可能为丁型肝炎病毒感染的高发区.在这些人群中,慢性活动性肝炎、慢性迁延性肝炎和肝硬化的抗-HD阳性率明显高于HBsAg携带者,但三者相互间差异无统计学意义,表明合并或重香感染HDV对乙肝慢性化及肝硬化的形成具有重要的意义。本研究证明在乙型肝炎病毒感染人群中丁型肝炎病毐与年龄、性别、职业等因素关系不密切。     

Seroprevalence of hepatitis delta virus infection among subjects with underlying hepatic diseases in Chennai, southern India

Four hundred million people are carriers of hepatitis B virus (HBV) worldwide and approximately 5% of these are reportedly positive for hepatitis delta virus (HDV). Several reports indicate a declining trend in the occurrence of HDV infection in the north of tropical India. To our knowledge, no study has been conducted to evaluate whether a similar epidemiological change is occurring in southern India. Therefore we evaluated the seroprevalence of HDV among 153 individuals with HBV-related liver diseases in Chennai, and assessed any change in epidemiological pattern by comparing the results with seroprevalence figures reported previously. Of the 153 patients screened, nine (5.9%) were reactive to anti-delta antibodies, six (3.9%) presented an evidence of past infection (IgG anti-delta positive) and three (2.0%) showed anti-HDV IgM, suggestive of recent HDV infection. Alanine transaminase elevation was not significant in HDV-associated infection compared with HBV alone-infected acute viral hepatitis (AVH) (P=0.82) and chronic liver disease (P=0.77) patients. The anti-HDV positivity in AVH was considerably low (6.6%), compared with previous Indian reports varying from 10.7% to >30%. HDV infection was relatively low and seems to play a minor determining factor of liver diseases in the tropical south Indian population.     

High prevalence of anti-hepatitis delta virus antibody in chronic liver disease in Somalia.

We have assessed the prevalence of hepatitis delta virus (HDV) infection in people with histologically proven chronic liver disease living in Somalia. Among 104 patients studied (14 with chronic persistent hepatitis, 74 with chronic active hepatitis, and 16 with active cirrhosis), 52 were positive for hepatitis B surface antigen; of these, 26 (50%) carried anti-delta antibodies. HDV infection was detected more frequently in sera from hepatitis B e antigen (HBeAg) negative patients (60.9%) than in HBeAg positive patients (9.1%). Using the dot-blot hybridization technique, serum hepatitis B virus deoxyribonucleic acid was revealed in 73.1% of patients without HDV infection, while it was detected in only 7.7% of anti-delta positive patients. It is concluded that HDV is strongly associated with chronic liver disease in Somalia.     

Delta virus and hepatitis B surface antigen in chronic liver diseases.

This work was carried out on 45 patients with chronic liver diseases, including 24 cases of liver cirrhosis and 21 cases of chronic hepatitis. Their ages ranged from 2 to 15 years (median 5). All cases were examined clinically and assessed biochemically for liver function tests. Serological studies were performed to detect hepatitis B surface antigen (HBsAg) and delta IgG antibody (IgG anti-HD) using Enzyme Immunoassay (EIA) technique. The study showed that IgG anti-HD was detected in 8.9% of cases with chronic liver diseases (all positive cases were with liver cirrhosis). On the other hand, HBsAg was detected in 53.3% of cases (54.2% of them with cirrhosis and 45.8% with chronic hepatitis) with no significant association between HBsAg positivity and type of hepatic illness. Moreover, IgG anti-HD was positive in only 4.2% of HBsAg positive cases, while 14.3% of HBsAg negative cases were positive for IgG anti-HD. A significant association was also found between delta positivity and serum glutamic oxaloacetic transferase level (SGOT). We concluded that chronic delta hepatitis appeared to be more severe than other types of chronic viral hepatitis, as all delta positive cases were with liver cirrhosis and had elevated SGOT levels. Screening of delta markers in addition to hepatitis B viral markers could improve the understanding of a number of obscure cases of chronic hepatic illnesses and would help in the control of HBV and consequently HDV infection in the general population.     

Immunization of woodchucks (Marmota monax) with hepatitis delta virus DNA vaccine

We investigated the DNA immunization approach in order to induce a protective immune response against hepatitis delta virus (HDV) superinfection of chronically woodchuck hepatitis virus (WHV) infected woodchucks. The animals were immunized with an expression vector encoding HDAg by gene gun. T cell and humoral immune responses induced by this protocol were determined and compared with those induced by HDAg immunization using a CpG oligonucleotide as an adjuvant. After immunization the woodchucks were challenged with 10⁶ genome equivalents of HDV. The protein immunization with HDAg induced good humoral and T helper cell responses in the woodchucks, but did not protect them from HDV superinfection. The DNA immunized woodchucks were also not protected from HDV superinfection, however, the course of infection was modified: HDV viremia occurred later, the typical fluctuation of the HDV RNA titer with several peaks was absent, and antibodies to HDV were not detectable.     

Immunization of woodchucks (Marmota monax) with hepatitis delta virus DNA vaccine

We investigated the DNA immunization approach in order to induce a protective immune response against hepatitis delta virus (HDV) superinfection of chronically woodchuck hepatitis virus (WHV) infected woodchucks. The animals were immunized with an expression vector encoding HDAg by gene gun. T cell and humoral immune responses induced by this protocol were determined and compared with those induced by HDAg immunization using a CpG oligonucleotide as an adjuvant. After immunization the woodchucks were challenged with 10⁶ genome equivalents of HDV. The protein immunization with HDAg induced good humoral and T helper cell responses in the woodchucks, but did not protect them from HDV superinfection. The DNA immunized woodchucks were also not protected from HDV superinfection, however, the course of infection was modified: HDV viremia occurred later, the typical fluctuation of the HDV RNA titer with several peaks was absent, and antibodies to HDV were not detectable.     

106例HBsAg携带者第7~12年追踪观察及影响转归因素的探讨

对106例HBsAg携带者进行了7~12年(平均9.5年)的随访。其转归:康复9例、急性肝炎3例,慢迁肝6例、慢活肝13例、肝硬变1例。死亡3例(原发性肝癌。慢性重症肝炎,食道癌各1例)、轻微肝功能损害12例。病后携带23例。无症状携带者36例,在观察期间,无肝炎史的93例携带者有40例发生急性肝炎,占43.0%。HBsAg阴转13例,阴转率为12.6%,阴转时间平均5.4年。高滴度HBsAs携带者和HBeAg阳性者,其HBsAg阴转率极显著低于低滴度携带者和HBeAg阴性者;而肝炎发病率、各种肝病发生率和肝功能异常率又显著高于后者。作者认为,HBsAg滴度高和伴有HBeAg是影响HBsAs携带者转归的重要因素。     

Immunization of woodchucks with adjuvanted sHDAg (p24): immune response and outcome following challenge

The immunogenicity and the protection induced by an hepatitis delta virus (HDV) vaccine consisting of the small nucleoprotein (HDAg) (p24) and adjuvanted with MF59 or Freund's adjuvant (FA) were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) and challenged with hepatitis delta virus. Humoral and T-cell-mediated responses to HDAg were measured. Anti-HD antibodies appeared earlier in the FA/p24 animals. After challenge, all MF59/p24 vaccinated animals showed a response to HDAg-derived peptides, compared to two of the five FA/p24 animals and one of the control animals. Serum HDV-RNA peak values and persistence were considerably reduced in immunized animals, in comparison to controls. Furthermore, HDV-RNA was absent in autopsy liver tissues of 50% of the MF59/p24 animals, whereas high levels were present in all of the FA/p24 animals and controls. Histological liver analysis performed before and after challenge revealed the presence of acute hepatitis-like lesions only in the controls. Overall, the results suggest that the MF59/p24 vaccine better controls the infection in terms of viral replication and survival.     

Anti-pre-S2 antibodies in natural hepatitis B virus infection and after immunization

Anti-pre-S2 antibodies were detected by enzyme-linked immuno-absorbant assay using a synthetic peptide analogue of pre-S2 protein, in different groups of hepatitis-B-infected subjects, including patients presenting with cirrhosis and liver cancer, and also in infants immunized with hepatitis B vaccine. Anti-pre-S2 antibodies were not detected in hepatitis B surface antigen (HBsAg) chronic carriers, including patients with cirrhosis or primary liver cancer. Anti-pre-S2 antibodies were not detected in HBsAg-positive sera during the early phase of acute hepatitis. They were only noted upon recovery, when anti-HBs antibodies are detectable at the same time as HBsAg. After recovery, anti-pre-S2 antibodies were noted in 57% of test sera and were still detectable in 16% of anti-HBs-positive sera obtained years after HBV infection. Anti-pre-S2 antibodies were detected in 70% of infants immunized with 2 or 5 micrograms doses of Hevac B Pasteur vaccine, confirming that this vaccine contains pre-S2 antigen. Anti-pre-S2 detection was correlated with the anti-HBs antibody titre.     

Transmission of hepatitis B and hepatitis delta viruses in the households of chronic hepatitis B surface antigen carriers: a regression analysis of indicators of risk

To evaluate whether clinical and laboratory features of a hepatitis B surface antigen (HBsAg) carrier can predict risks of infection, its chronicity, and the development of liver disease among close contacts, the authors studied a cohort of 994 first degree relatives or cohabitants (household contacts) of 226 non-drug-addicted chronic HBsAg carriers (index cases), of whom 77% had liver disease and 26% were superinfected by hepatitis D virus (HDV). A logistic form of regression analysis was used to assess the role of each feature in the index case as predictor of hepatitis B virus (HBV)- and HDV-related outcomes among household contacts. Six models of risk, expressed as odds ratios, were assessed by multivariate step-down analysis, with the following results. 1) Infection with HBV in the household contact was independently predicted by the index case being son, sibling, spouse, female, or HBV-DNA positive. 2) Chronic HBsAg carriage in the adult household contact was associated with female sex of the index case and with being a sibling; among young subjects, household contacts were more likely to be chronic HBsAg carriers when the index case was the mother, a sibling, or an HBV-DNA-positive subject. 3) HBV-DNA positivity in the young contact was more likely when the index case was HBV-DNA positive and when she was the mother. 4) HBV-DNA positivity in the absence of hepatitis B e antigen (HBeAg) in serum in the index case was not related to a similar pattern of infection in HBsAg-positive contacts. 5) Super-infection with HDV of an HBsAg-positive household contact was significantly predicted by female sex of the index case and by anti-HDV positivity. 6) Chronic liver disease in a contact was predicted only by HDV superinfection of the index case. We conclude that horizontal, nonparenteral transmission of HBV among siblings plays a major role in the household of HBsAg carriers from an intermediate endemicity area.     

丁型肝炎病毒抗原酶联免疫诊断试剂盒（HDAG—E）的制备和应用

为了建立丁型肝炎病毒抗原酶联免疫诊断试剂,选用慢性肝炎患者的高效价抗-HD阳性血清用亲和层析法进行纯化;选用吐温20为裂解液处理血清,以裸露HDV核心部位的HDAg。本试剂采用酶联夹心法。经与澳大利亚及荷兰HEPAnoST1KA试剂盒HDAg对比,结果完全一致。与甲、乙型肝炎病毒抗原无交叉反应。用抗-HD阳性血清作中和试验确认其特异性可靠。对本院各类HBsAg阳性的肝炎患者或携带者血清测定结果,其HDAg的检出率为2.29％(9/392);国内8省、市同类病例HDAg检出率为1.37％(10/729)。临床及流行病学调查表明,本试剂可靠、实用。