Hepatitis B virus replication in acute hepatitis B, acute hepatitis B virus-hepatitis delta virus coinfection and acute hepatitis delta superinfection

To evaluate the effect of hepatitis delta virus on the level of replication of hepatitis B virus and to assess the clinical significance that such an effect might have on the final outcome of the infection, the serological profile of hepatitis B virus DNA was investigated in 153 patients with acute or chronic hepatitis B virus infection with or without associated delta infection. Serum hepatitis B virus DNA was detected in 57% of patients with acute hepatitis B, 67% of those with acute hepatitis B virus-hepatitis delta virus coinfection and 25% of HBsAg carriers with hepatitis delta virus superinfection during the first week after the onset of symptoms. Patients with acute hepatitis B and those with acute hepatitis B virus-hepatitis delta virus coinfection did not differ significantly with respect to the serological profile of hepatitis B virus DNA and final clinical outcome. Within the group of HBsAg carriers with hepatitis delta virus superinfection, all patients who were initially negative for hepatitis B virus DNA developed chronic hepatitis delta virus infection, whereas 3 of the 4 patients with active hepatitis B virus infection at the time of superinfection showed transient inhibition of hepatitis B virus replication followed by termination of hepatitis delta virus infection in two patients. Therefore, although delta virus may inhibit the replication of hepatitis B virus among chronic HBsAg carriers, this effect is not readily apparent among patients with hepatitis B virus-hepatitis delta virus coinfection.     

Hepatitis B virus DNA, HBeAg and delta infection during the course from acute to chronic hepatitis B virus infection

The presence of hepatitis B virus DNA in serum was determined in 57 unselected patients during the course from acute to chronic hepatitis B infection. Forty-six (81%) patients were hepatitis B virus DNA-positive in the first available serum sample. Generally, hepatitis B virus DNA was cleared before or at the same time as HBeAg, but in two patients (4%), hepatitis B virus DNA could be demonstrated after HBeAg clearance. One of the latter patients had hepatitis B virus DNA in the presence of anti-HBe. Both patients became hepatitis B virus DNA-negative. Seven of the hepatitis B virus DNA-positive patients received long-term treatment with prednisone, and three of them continued to be hepatitis B virus DNA positive for more than 10 years. Among the untreated patients hepatitis B virus DNA could be detected for up to 7 years, and 10 patients were hepatitis B virus DNA-positive for three years or more. Twenty-four patients (42%) showed serological signs of delta agent infection. Hepatitis B virus DNA clearance was observed in a significantly higher proportion (87%) of delta-infected patients as compared to patients with no delta infection (45%) (p less than 0.05). In addition patients with delta infection had a significantly increased hepatitis B virus DNA clearance rate as compared to patients without delta markers in their serum (p less than 0.01). In one (8%) delta-infected patient, hepatitis B virus DNA clearance was followed by a fall in transaminases into the normal range as opposed to results in 86% of patients with pure hepatitis B (p less than 0.002).     

Evidence for hepatitis B and other virus infection in HBsAg-negative chronic active hepatitis

Antibody to the hepatitis B core antigen (anti-HB_c) was detected in sera from 6 (19%) of 32 patients with HB_sAg-negative chronic active hepatitis. In three cases with the highest anti-HB_c titers, core antigen was detected in liver cell nuclei and in one case HB_sAg was also present in hepatocytes, suggesting continuing hepatitis B virus infection. During follow-up, anti-HB_c titers fell slowly in those with no viral antigens in liver tissue, and in two cases with virus in the liver at presentation, viral antigens were no longer demonstrable four and eight years later. In one case, clearance of virus was preceded by the appearance of HB_sAg in liver and serum, suggesting reactivation of viral replication. In three of the anti-HB_c-negative cases a nuclear antigen unrelated to the hepatitis B virus was detected by immunofluorescence, and it is possible that liver disease in these patients may be related to persistent non-A, non-B virus infection.     

Hepatitis C virus infection in patients with acute hepatitis B

The prevalence of antibodies to hepatitis C virus (anti-HCV) was studied using a second-generation ELISA test in 121 patients with self-limiting acute hepatitis B, including 63 intravenous drug addicts (IVDA). Within the first month after the onset of illness, 47.1% of the patients were anti-HCV positive, this figure reaching 52.1% six months later. The prevalence in the sixth month was significantly higher in the IVDA (93.6%) than in the non-IVDA (6.9%) (p < 0.00001). Among the IVDA, anti-HCV was more frequent in those with (100%) than in those without hepatitis delta virus (HDV) coinfection (84.6%) (p = 0.004). Of the 63 anti-HCV positive patients, 36 (57.1%) continued to exhibit abnormal transaminase levels for more than six months, while this was not observed in anti-HCV negative patients. These results show a high prevalence of infection by hepatitis C virus (HCV) in IVDA with acute B hepatitis. As a rule, infection by HCV occurred prior to the hepatitis B infection, although occasionally simultaneous infections were observed. HCV appears to be the agent responsible for chronic liver disease in patients with acute B hepatitis who become HBsAg negative.     

Hepatitis B virus and delta infection in male homosexuals

Six hundred and sixty-six homosexuals were analysed in respect of hepatitis B virus and delta infections. Evidence of ongoing or recent hepatitis B virus infection was found in 450/666 (67.6%) homosexuals; 44 were HBsAg positive. Anti-delta was found in two HBsAg-positive homosexuals. Both individuals had a non-replicative form of HBV infection and biochemical evidence of liver disease. The study confirms that HBV infection is frequent in homosexuals and indicates that delta-infection is rare in male homosexuals.     

Hepatitis B virus and hepatitis C virus dual infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) share common mode of transmission and both are able to induce a chronic infection. Dual HBV/HCV chronic coinfection is a fairly frequent occurrence, especially in high endemic areas and among individuals at high risk of parenterally transmitted infections. The intracellular interplay between HBV and HCV has not yet been sufficiently clarified, also due to the lack of a proper in vitro cellular model. Longitudinal evaluation of serum HBV DNA and HCV RNA amounts has revealed that complex virological profiles may be present in coinfected patients. Dual HBV/HCV infection has been associated to a severe course of the liver disease and to a high risk of developing hepatocellular carcinoma. Despite the clinical importance, solid evidence and clear guidelines for treatment of this special population are still lacking. This review summarizes the available data on the virological and clinical features as well as the therapeutic options of the dual HBV/HCV infection, and highlights the aspects that need to be better clarified.     

A possible misdiagnosis in patients presenting with acute HBsAg-negative hepatitis: the role of hepatitis delta virus

Summary We describe here two cases of delta hepatitis (a coninfection and a superinfection) presenting as acute HBsAg-negative hepatitis. The first patient, a parenteral drug abuser, had a biphasic course of the disease, with HBsAg detectable transiently only during the relapse. Testing for delta markers on stored sera gave evidence of HBV/HDV coinfection. The other patient, a hospital nurse, chronic asymptomatic carrier of HBsAg, developed fulminant hepatitis with the transient appearance of antibody to HBsAg. She survived massive liver necrosis, and serological analysis of HDV markers documented a hepatitis delta virus superinfection. These cases demonstrate the possible substantial repression of HBV gene products exerted by the replication of delta virus, with a likely misdiagnosis if delta markers are not determined in serial serum samples.

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Fehldiagnose bei akuter, HBsAg-negativer Hepatitis: Rolle des Hepatitis Delta Virus

Zusammenfassung Wir beschreiben zwei Fälle von Delta Hepatitis (eine Koinfektion und eine Superinfektion), die als akute, HBsAg-negative Hepatitis auftraten. Bei dem ersten Patienten, einem i. v. Drogenabhängigen, hatte die Krankheit einen biphasischen Verlauf. HBsAg war nur vorübergehend, während des Rückfalls, nachweisbar. Die Untersuchung der aufbewahrten Serumproben auf Delta-Marker erbrachte den Beweis für eine HBV/HDV-Koinfektion. Im zweiten Fall hatte eine Krankenschwester, die asymptomatische Trägerin von HBsAg ist, eine fulminante Hepatitis entwickelt, während der die Antikörper gegen HBsAg vorübergehend verschwanden. Sie überlebte eine massive Lebernekrose. Die Serumuntersuchung auf HDV-Marker belegte eine Hepatitis Delta Virus-Superinfektion. Die beiden Fälle zeigen, daß es durch die Replikation des Delta-Virus zu einer erheblichen Beeinträchtigung der Genexpression des HBV kommen kann, was zu diagnostischen Fehlschlüssen führt, wenn nicht in Serum-Serienproben eine Testung auf Delta-Marker erfolgt.

     

HBsAg-negative mono-infection with hepatitis B virus genotype G

Infection with a genotype G strain of hepatitis B virus (HBV-G) often occurs as a co-infection with HBV genotype A. In mono-infection with HBV-G, the production of hepatitis B surface antigen (HBsAg), HBe antigen and anti-HBe seems diminished, hampering the serological diagnosis of HBV-G mono-infection. To corroborate this notion, we studied in detail a series of samples of a blood donor with transient HBV-G infection. In this donor, during the temporary presence of HBV DNA and the seroconversion to HBcore antibodies (anti-HBc), no HBsAg or hepatitis B e antigen was detected. During follow-up, no anti-HBe appeared. Multiple resistance mutations to lamivudine were present, demonstrating primary infection with a resistant HBV strain. Cloning and sequencing indicated that no other HBV genotype but genotype G was present. Like other HBV-G isolates, the DNA sequence of the HBsAg a-determinant showed no mutations that could explain the failure to detect HBsAg. Our findings demonstrate that HBV genotype G mono-infection occurs and that routine serology is unsuitable for its detection.     

Correlation between Hepatitis delta virus infection and heptitis B virus serum markers

AIM: To analyse the correlation between HDV infection and HBV serum markers. METHODS: Patients who were positive for HBV serum markers were selected and HDV infection was examined in them. Blood donors were used as a control group. Both HDV infection and HBV serum markers were tested by enzyme-linked immunosorbent assay. RESULTS: HDV infection was detected in 40 of 289 patients who were positive for HBV serum markers. The overall positive rate of HDV infection was 13.8%. The positive rates of HDV infection in HBsAg(+) group, HBcAb(+) group and HBeAb(+) group were 17.6%, 18.8% and 25.2%, respectively, which were higher than that in HBeAg(+) group (10.9%), and none was detected in HBsAb(+) group. HDV infection appeared in HBsAg(+)HBcAb(+)HBeAb(+) patients with a positive rate of 26.2%, which was much higher than that in HBsAg(+)HBcAb(+)HBeAg(+) patients (10.9%). CONCLUSION: HDV coinfection is more frequent in HBsAg(+) HBcAb(+)HBeAb(+) patients than in BsAg(+)HBcAb(+)HBeAg(+) patients. HDV infection is not completely related with the speed and amount of HBV replication.     

Prevalence of markers of hepatitis B virus infection or vaccination in HBsAg-negative subjects

Background.

The implementation of mass vaccinations against hepatitis B virus (HBV) has significantly reduced the prevalence of HBsAg-positive subjects. At the same time, the prevalence of the other markers of infection has decreased, but there has been an increase in the percentage of subjects with markers of a successful vaccination. It has been suggested that increasing immigration from countries in which this virus is highly endemic is changing the epidemiology of HBV infection. The aim of this study was to assess the prevalence of the serological markers of HBV in Italian and non-Italian HBsAg-negative subjects.

Materials and methods.

In the years 2007–2008, 8,018 samples from HBsAg-negative subjects (7,521 Italians and 497 non-Italians) were received for detection of anti-HBs and/or anti-HBc. The findings in the 1,358 samples from candidate blood donors were compared with those obtained in 1991 and 1999.

Results.

The rate of anti-HBc positivity was 18.3% in the Italian samples and 32.8% in the non-Italian samples; the corresponding percentages of anti-HBs/anti-HBc positive samples (indicating past infection), anti-HBs positive only samples (vaccination) and anti-HBc positive only were, 11.3% vs. 22.5%, 25.8% vs. 17.2%, and 6.9% vs. 9.9% in Italians and non-Italians, respectively. The differences were more marked when stratified by age. In relation to candidate blood donors, simultaneous positivity for anti-HBs and anti-HBc decreased from 11.0% in 1991 to 8.1% in 1999 and 3.9% in 2007–2008, whereas isolated anti-HBs positivity increased from 2.2% in 1991 to 21.4% in 1999 and 42.9% in 2007–2008.

Conclusions.

The frequency of markers of past infection among Italians has decreased over time as a result of mass vaccination and is significantly lower than that observed in non-Italians. The increasing number of immigrants from countries in which HBV is highly endemic is changing the epidemiology of HBV infection in Italy.     

Hepatitis D virus RNA in acute delta infection: serological profile and correlation with other markers of hepatitis D virus infection

To evaluate the profile of hepatitis D virus replication and the corresponding immunoresponse after acute hepatitis D virus infection, sera from 50 patients with acute hepatitis D (36 with acute hepatitis B virus-hepatitis D virus coinfection and 14 HBsAg carriers with hepatitis D virus superinfection) were investigated for the presence of hepatitis D virus RNA and other serological hepatitis D virus markers. During the first week after onset of symptoms, hepatitis D virus RNA was detected by spot hybridization with a similar frequency among patients with coinfection (64%) and those with superinfection (71%). The presence of hepatitis D virus RNA in the first serum sample correlated with that of circulating hepatitis D antigen in both groups of patients. The presence of hepatitis D virus RNA was transient and its clearance paralleled that of serum hepatitis D antigen among patients with coinfection, so that 1 month after the onset of symptoms serum hepatitis D virus RNA was no longer detectable in any of these patients. Conversely, serum hepatitis D virus RNA was still present in 78% of those with superinfection, all of whom developed chronic liver disease, thus suggesting that the persistence of hepatitis D virus RNA in the serum for more than 4 weeks might indicate progression to chronicity. In nine of the 14 patients (64%) with hepatitis D virus superinfection progressing to chronicity, hepatitis D virus RNA was persistently detected throughout the follow-up, whereas in five patients it was detected occasionally. In four superinfected patients hepatitis D virus RNA and hepatitis B virus DNA were detected simultaneously in serial samples, thus suggesting that, at least during early stages of chronic hepatitis D virus infection, both viruses may replicate at the same time.     

Hepatitis B virus of genotype C persistence after recovery from acute hepatitis B virus infection in Japan

Background/aims: this study aimed to determine the viremia status after clinical, biochemical and serological recovery from acute hepatitis B viral (HBV) infection. Methods: we detected serum HBV-DNA in 19 patients with acute hepatitis B during followed-up 6–43 months after onset, and analyzed HBV genotypes. Results: 13 (72%) of 19 patients had detectable HBV DNA at the point of 6 months after onset, and four (33%) of 12 patients had persisted viremia for more than 1 year although they were recovery with normalization of alanine transaminase (ALT), disappearance of hepatitis B surface antigen (HBsAg) and appearance of antibody against HBsAg (anti-HBs). Eighteen (95%) of 19 patients were infected with HBV genotype C, one (5%) with genotype B. Conclusions: these results suggest genotype C of HBV is the predominant genotype of acute hepatitis B in Nagasaki region in Japan. HBV can persist in the serum for more than one year after complete clinical and serological recovery from acute viral hepatitis.     

Hepatitis B virus and hepatitis C virus infection in healthcare workers

Approximately 3 million healthcare workers per year receive an injury with an occupational instrument, with around 2000000 exposures to hepatitis B virus(HBV) and 1000000 to hepatitis C virus(HCV). Although an effective HBV vaccine has been available since the early eighties, and despite the worldwide application of universal vaccination programs started in the early nineties, HBV still remains a prominent agent of morbidity and mortality. There is no vaccine to limit the diffusion of HCV infection, which progresses to chronicity in the majority of cases and is a major cause of morbidity and mortality worldwide due to a chronic liver disease. Healthcare workers are frequently exposed by a mucosal-cutaneous or percutaneous route to accidental contact with human blood and other potentially infectious biological materials while carrying out their occupational duties. Mucosal-cutaneous exposure occurs when the biological material of a potentially infected patient accidentally comes in contact with the mucous membranes of the eyes or mouth or with the skin of a healthcare worker. Percutaneous exposure occurs when an operator accidentally injures himself with a sharp contaminated object, like a needle, blade or other sharp medical instrument. About 75% of the total occupational exposure is percutaneous and 25% mucosal-cutaneous, the risk of infecting a healthcare worker being higher in percutaneous than in mucosal-cutaneous exposure. All healthcare workers should be considered for HBV vaccination and should meticulously apply the universal prophylactic measures to prevent exposure to HBV and HCV.     

Hepatitis B virus infection among household contacts of patients with acute HBsAg-positive hepatitis

Summary Sixty-seven household contacts of 31 index cases with acute HBsAg-positive hepatitis were investigated forHepatitis B virus (HBV) markers. Follow-up findings in 50 household contacts revealed that six spouses and/or sexual partners had developed acute clinical hepatitis B. Three of these six contacts were drug addicts. A further seven contacts showed serological changes compatible with exposure to HBV, but had no signs of acute clinical hepatitis. Six of these seven contacts were spouses and/or sexual partners of their index case. Possible prophylactic or post-exposure measures only seem to be necessary in the spouses and/or sexual partners of patients with acute hepatitis B.

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Hepatitis-B-Virus-Infektion bei Personen mit Familienkontakt zu Patienten mit akuter HBsAg-positiver Hepatitis

Zusammenfassung Siebenundsechzig Personen, die in häuslichem Milieu Kontakt zu 31 Fällen mit akuter HBsAg-positiver Hepatitis hatten, wurden auf Hepatitis-B-Virus (HBV) Marker untersucht. In Verlaufskontrollen bei 50 Personen mit Kontakt zu den Hepatitis-Kranken zeigte sich, daß sechs Ehegatten und/oder Geschlechtspartner eine klinisch akute Hepatitis B entwickelt hatten. Weitere sieben Kontaktpersonen wiesen serologische Veränderungen auf, die mit einer Exposition gegenüber HBV vereinbar waren; doch hatten diese Personen keine klinisch manifeste Hepatitis. Sechs dieser sieben Kontaktpersonen waren Ehegatten und/oder Geschlechtspartner des jeweiligen Hepatitisfalles. Prophylaktische oder therapeutische Maßnahmen nach Exposition scheinen nur bei Ehegatten und/oder Geschlechtspartnern von Patienten mit akuter B-Hepatitis erforderlich zu sein.

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Other members of the group:P. Christoffersen, O. Dietrichson, V. Faber, C. Gluud, G. Høybye, K. Iversen, E. Juhl, P. Kryger, L. R. Mathiesen, P. Petersen, H. Poulsen, P. Schlichting, P. Skinhøj, T. I. A. Sørensen.     

HBsAg-negative hepatitis B virus infections in hepatitis C virus-associated hepatocellular carcinoma

This study was conducted to evaluate reports that hepatitis B virus (HBV) DNA sequences can be found in the serum and/or tumour tissue from some hepatocellular carcinoma (HCC) patients who have no detectable hepatitis B surface antigen (HBsAg) in their sera. Such HBV infections would be highly atypical, because prospective studies have shown a clear succession of specific serologic markers during and after most HBV infections. As most HBsAg-negative HCC patients in Japan have hepatitis C virus (HCV) infections, the present study was conducted to determine whether some of these patients actually have unrecognized HBV infections. Thirty newly diagnosed HCC patients from Kurume, Japan, with antibody to the hepatitis C virus (anti-HCV) were studied. None of the 30 had HBsAg detectable in their serum. Of 22 for whom test results for antibodies to the hepatitis B core antigen (anti-HBc) and antibodies to HBsAg (anti-HBs) were available, 14 (64%) had anti-HBc and anti-HBs, four (18%) had anti-HBc alone, and four (18%) had no HBV markers. Nested polymerase chain reaction was used to detect the HBV surface (S), core (C), polymerase (P) and core promoter gene sequences in the HCC tissues and in the adjacent nontumorous liver tissues. HBV DNA was detected in HCC and/or adjacent nontumorous liver in 22 of 30 (73%) patients [detected in both HCC and nontumorous liver in 19/30 patients (63%)]. Among the 22 patients with detectable HBV DNA, more than one HBV gene was detected in 10 (46%). Among the four patients whose sera were negative for all HBV markers, three had HBV DNA in either HCC and nontumorous liver (two cases) or only in the nontumorous liver (one case); HBV DNA could not be detected in tissues from the fourth patient. In 18 of 21 (86%) patients with detectable HBV core promoter sequences, mutations at both nucleotides 1762 (A-GT) and 1764 (G-A) in the core promoter region were found. No deletions were detected in the core promoter gene region of the type reported to be associated with some cases of HBsAg-negative HBV infection. Thus, HBV DNA was detectable in 22 (73%) HBsAg-negative, anti-HCV-positive HCCs, including three (10%) who were also negative for anti-HBc and anti-HBs. HBV mutations at both nucleotides 1762 (A-GT) and 1764 (G-A) in the core promoter region were found in the majority of cases, mutations that have previously been reported in HBV that is integrated in HCC DNA. In serologic surveys to determine etiologic associations of HCC, patients such as those in this study would have been incorrectly designated as having 'HCV-associated HCC,' whereas the data in this study suggest that HBV could have played a role in the development of their HCCs.