HBV Superinfection Research Articles

Hepatitis B-related acute-on-chronic liver failure induced by hepatotropic viral insult is associated with worse prognosis than that induced by non-virus insult

BackgroundThe manifestations and prognoses of acute-on-chronic liver failure (ACLF) with different precipitating events remain heterogeneous. We aimed to investigate the characteristics and prognosis of patients with hepatotropic viral insult (HVI)-induced hepatitis B-related ACLF (HBV-ACLF).Methods452 patients with confirmed diagnosis of ACLF were screened in three medical centers in China, and 203 HBV-ACLF patients with definite acute precipitating events were retrospectively analyzed. According to the precipitating events, HBV-ACLF patients induced by HBV reactivation and super-infection with HAV were classified as the hepatotropic viral insult group and those induced by other factors, as the non-virus insult (NVI) group. The clinical characteristics, predictive scoring model, and prognosis of the two groups were compared.ResultsHepatitis B virus reactivation accounted for the largest proportion (39.9%) among all precipitating events. Exacerbation time frame of the HVI group was significantly longer than that of the NVI group (20 days vs. 10 days, P < 0.001). Comparison of intergroup prognosis showed that there was no significant difference in the 28 day mortality (20.9 vs. 13.7%, P = 0.125), while the 90 day and 1 year mortality in the HVI group were higher than those in the NVI group (36.3 vs. 24.4%, P = 0.014; 39.5% vs. 27.5%, P = 0.020, respectively). In the HVI group, the lactic acid-free APASL-ACLF Research Consortium (AARC) had better predictive value for 90 day mortality (0.741).ConclusionsThe 90 day and 1 year survival rate was lower in HBV-ACLF patients induced by HVI than by NVI. The lactate-free AARC score was a better predictor of short- and long-term prognosis in patients with HVI-induced HBV-ACLF.

Hepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues.

Background:Only limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation.Methods:We retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes.Results:Chronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection.Conclusions:A significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance.

Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection

Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV in vivo and whether infectious HDV could subsequently be released following HBV super-infection. Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry. The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 10(8) HDV RNA and 10(7) HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice. HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation.

452 IN VIVO INHIBITORY EFFECTS OF HEPATITIS B VIRUS X PROTEIN ON LIVER REGENERATION THROUGH A IL-6 DEPENDENT MECHANISM

Results: Endogenous expression of L-, S-, coreor HBe-protein did not result in a significant interference with the subsequent infection with HDV. However, expression of L-protein drastically reduced HBV infection efficacy. In contrast, S-protein expression had only marginal effect on both viruses. By mutation analysis on the preS-domain, we found that deletions in the capsid binding region restored the susceptibility to HBV infection. Conclusions: The presence of preS-domain of L-protein specifically interferes with HBV superinfection through its capsid binding domain. This is not due to a regulation of virus receptor since the HDV infection remains unaffected. We hypothesize that the released incoming nucleocapsid might be hindered from trafficking to the nucleus by pre-existing L-protein. Thus, L-protein might act as a regulator of intracellular nucleocapsid trafficking in order to discriminate between HDV and HBV superinfection.

454 PRODUCTION AND CHARACTERIZATION OF HEPATOTROPIC HEPATITIS B VIRUS (HBV) PRES1-INTERFERON a (IFNa) FUSIONS FOR TARGETED ANTIVIRAL THERAPIES

Results: Endogenous expression of L-, S-, coreor HBe-protein did not result in a significant interference with the subsequent infection with HDV. However, expression of L-protein drastically reduced HBV infection efficacy. In contrast, S-protein expression had only marginal effect on both viruses. By mutation analysis on the preS-domain, we found that deletions in the capsid binding region restored the susceptibility to HBV infection. Conclusions: The presence of preS-domain of L-protein specifically interferes with HBV superinfection through its capsid binding domain. This is not due to a regulation of virus receptor since the HDV infection remains unaffected. We hypothesize that the released incoming nucleocapsid might be hindered from trafficking to the nucleus by pre-existing L-protein. Thus, L-protein might act as a regulator of intracellular nucleocapsid trafficking in order to discriminate between HDV and HBV superinfection.

Determination of Hepatitis Delta Virus Genotype among HBV Carriers in Southwest of Iran

Background and Aims: HDV is a defective satellite virus and classified in genus Deltavirus. Its disease is related and limited to HBV-infected patients. Acute infection of delta agent occurs in two different patterns; simultaneous infection with both HBV & HDV or super infection of chronically HBV infected patients that lead to more sever type of hepatitis. According to genetic diversity of genomic RNA of HDV, 8 clades have been classified. The aim of this study was to determine the delta virus genotype among the HBV & HDV infected patients in Ahvaz city. Materials and Methods: Sera sample collected from 31 seropositive HDV patients including 21 male and 9 female mean age 46±13.5 suffering from chronic hepatitis and 1 male patient with acute hepatitis. The encoding region for C terminal half of the Delta anti gene of the HDV’s genomic RNA reverse transcribed and then amplified by nested PCR. The HDV PCR positive samples were sequenced, and the sequences were compared with reference sequences on GenBank. All samples were tested for HBV DNA, HCV RNA and HCV anti body. Results: Only 15(48%) out of 31 anti HDV seropositive patients were positive for HDV RNA by nested RT-PCR. Alignment and phylogenic analysis of the present HDV sequences revealed that all sequences belong to clade 1. Only 1 HDV RNA positive patient was positive for HBV DNA by nested PCR. Conclusion: According to previous studies the clade 1 (genotype 1) is the predominant clade of HDV in our country. However some (2-HDV-R, 4-HDV-R &11-HDV-R) of our isolates show extensive differences from the two previously isolated HDVs from Iran. Most of the our isolates were closely related to the Iranian HDVs, but Egyptian HDV still remains the most relevant foreign isolate. Suppression of HBV replication by delta virus is common but mutual suppression of HDV and HCV remains unclear.

Sustained remission of chronic hepatitis C after acute hepatitis B superinfection

We observed acute HBV superinfection on chronic HCV genotype 1 infection in a 29-y-old injection drug user. On presentation HCV-RNA was already negative and remained so for at least 7 months thereafter. We speculate that clearance of HCV-HBV coinfected cells by HBV-specific immunity might be a mechanism of HCV eradication.

Candidates for therapy: HBV

Hepatitis B may cause liver damage ranging from mild chronic hepatitis to severe active hepatitis, cirrhosis and hepatocellular carcinoma. HIV and HBV co-infection is more likely to lead to lower rates of HBeAg seroconversion, and higher HBV DNA concentrations. Immune restitution may lead to more severe hepatitis. The timing of acquisition of HBV versus HIV will have a bearing on considerations of treatment. Patients may have acquired HIV super-infection of chronic hepatitis B, HBV super-infection of HIV; alternatively, reactivation of hepatitis B may occur in a HIV positive patient, or the patient may be co-infected at diagnosis. The patient may be naïve or experienced or have resistant (HBV) at the time of superinfection. The risk of death is higher in patients with co-infection compared to those with HBV alone. The goals of therapy for hepatitis B are to prevent progression of the disease. If HBV replication can be suppressed, the accompanying reduction in histological activity lessens the risk of progression. Patients may request treatment to reduce infectivity, and this is relevant in co-infected patients. HBV has little effect on HIV or the effect of treatment on HIV; however, HIV, and HIV treatment profoundly affects the natural history of HBV. Therefore, it is usually important to target treatment of HBV to alter the outcome and take into account the impact of HBV treatment on HIV. Special concepts of treatment are applicable in HIV and HBV co-infected patients.

HBV superinfection in HCV chronic carriers

HBV superinfection in HCV chronic carriers

Detection of serum hepatitis B, C, and D viral nucleic acids and its implications in hepatocellular carcinoma patients.

The association of viremia, elevated serum alanine aminotransferase (ALT) levels, and hepatocyte inflammatory activity in hepatocellular carcinoma (HCC) patients was studied. Serum samples from 114 HCC patients undergoing surgery were assayed for hepatitis B, C, and D viral nucleic acids by polymerase chain reaction (PCR) prior to surgery. Of these patients, 65 had HBV infection alone, 15 had HCV infection alone, 4 had HDV infection, 20 had HBV and HCV superinfection, 1 had triple viral infection, and 9 were negative for HBV and HCV infections. The prevalence of active viral replication was significantly higher in HCV than in HBV (92% versus 70%; P = 0.006) patients, and significantly higher mean serum ALT levels were also noted in the HCV group than in the HBV group (P = 0.02). The incidence of marked ALT elevation (>200 U/l) was highest in the HCV (27%) and the HDV (25%) groups. Patients in the HCV group were 10 years older than those in the HBV group. Viral superinfection did not accelerate the development of HCC. Viral replication persisted in a significant portion of HCC patients and a higher prevalence of hepatic inflammation was noted in patients with HCV- and, possibly, HDV-related HCC.

Etiology of acute exacerbation in patients with severe chronic active hepatitis by in situ HBVDNA hybridization technique

To explore etiology of acute exacerbation in severe chronic active hepatitis, in situ HBVDNA hybridization was carried out combined with detection of HBV markers in the serum and the liver as well as intrahepatic HDAg in 15 cases. Four subgroups were identified based on the etiological evidence: 1) 9 cases were still undergoing HBV active replication or reactivation with cytoplasmic and membraneous HBcAg expression, often associated with the hepatic necrosis foci; 2) 3 cases showed HBsAg or/and HBVDNA positivity despite absence of HBcAg expression, the membranous and homogeneous HBsAg expression being closely related with hepatic necrosis; 3) 2 cases were HDAg positive; 4) the remaining case exhibited no HBV infection evidence. All findings suggested that HBV active replication or reactivation was the major cause of the exacerbation in severe chronic active hepatitis. In addition, HBV superinfection accounted for over 10% of cases with acute exacerbation. Hepatitis A or C may contribute to some episodes of exacerbation.

Follow-up studies on IgM anti-HBc during chronic hepatitis B

Sera of 190 HBsAg positive chronic hepatitis B patients were followed up for IgM class antibodies to hepatitis B virus core antigen (IgM-anti-HBc) by a commercial ELISA (Abbott) as well as a 19S(IgM) RIA until these antibodies were no longer detectable. IgM anti-HBc was detected only up to two of five years after onset of acute disease. The periods of detectable IgM anti-HBc in 34 chronic persistent and 36 chronic active hepatitis B (CPH, CAH) patients did not differ significantly on the basis of chi 2-test. 56% of the CPH and 47% of the CAH patients showed markers of infectivity in the sera recently cleared of IgM anti-HBc. Sera of both the IgM anti-HBc positive CPH and CAH patients had on the average fivefold elevated aminotransferase (SGPT) activity. In sera recently cleared of IgM anti-HBc, mean SGPT activity was detected twofold the normal value in CPH and threefold in CAH patients. Inflammatory activity in the liver biopsies was seen highly increased both in the IgM anti-HBc positive CPH and CAH patients. Fibrosis was most progressed and cirrhosis observed mainly in the liver biopsies of the IgM anti-HBc cleared CAH patients. In 3 IgM anti-HBc cleared chronic hepatitis B patients (CPH n = 1, CAH n = 2) converted to anti-HBe, IgM anti-HBc was detectable anew after a HBV superinfection with other HBsAg subtypes.

CORRELATION OF VIROLOGICAL AND CLINICAL PROFILE OF PATIENTS WITH CHRONIC HEPATITIS B &amp; C CO-INFECTION

Background: Both HBV super-infection in patients with chronic hepatitis C and HCV super-infectionin patients with chronic hepatitis B have been reported. In case of co-infection, hepatitis B and C interactwith each other and affect immune responses resulting in active HCV with inactive HBV, active HBVwith inactive HCV, both active and both inactive. The objective of our study was to find out andcorrelate the virological and clinical profile in our patients with chronic hepatitis B and C co-infection.Material and Methods: This observational, descriptive and cross-sectional study was conducted atMedical ‘A’ Ward, PGMI, LRH Peshawar and Author’s Private Hepatology Clinic, from July 2010 toJune 2014. All patients with HBsAg and Anti-HCV Reactive by ELISA for more than six months wereincluded in the study. Following investigations were carried out in these patients: Serum ALT, HBeAg,anti-HBe, HBV DNA PCR, HCV RNA PCR, and abdominal ultrasound. Data was entered and analyzedusing SPSS version 16.0.Results: A total of 130 patients were included in the analysis, out of which 81 (62.3%) were males.Mean age of patients was 40.52±14.27 years. Majority of patients belonged to age-group of 21-30 years.Mean serum ALT of patients was 83.69±60.48 U/L. Majority of patients belonged to ALT-Group of 41-80 U/L. Hepatitis C Virus was the dominant virus in 53% of patients. Chronic Hepatitis was thedominant clinical profile in 73% of patients.Conclusion: Hepatitis C Virus is the dominant virus in our patients with BC co-infection. There is nostatistically significant association between virological and clinical profile of these patients.Key Words: Hepatitis B Virus, Hepatitis C Virus, BC Co-infection, Chronic Hepatitis, Cirrhosis,Hepatocellular Carcinoma