scholarly journals Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

2020 ◽  
Author(s):  
Laetitia Canini ◽  
Yuji Ishida ◽  
Masataka Tsuge ◽  
Karina Durso-Cain ◽  
Tje Lin Chung ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Adaptive Immune Response ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Interferon Α ◽  
Adaptive Immune ◽  
B Virus

AbstractBackgroundWhereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during pegylated interferon-α-2a (pegIFN), LAM and pegIFN+LAM treatment of chronically HBV-infected humanized uPA/SCID chimeric mice.MethodsThirty-nine uPA/SCID mice with humanized livers whose pre-treatment steady-state serum HBV reached 9.2±0.4 logIU/mL were treated with pegIFN, LAM or pegIFN+LAM for 14 days. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a nonlinear mixed effect viral kinetic model and simultaneously fit it to the serum and intracellular HBV DNA data.ResultsUnexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Modeling predicts that the first phase represents pegIFN inhibiting intracellular HBV DNA synthesis with efficacy of 86%, which was similar under LAM and pegIFN+LAM. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN+LAM (0.46/d) and the slowest (0.052/d) during pegIFN mono-treatment.ConclusionsReminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production; however, enhancement of second phase decline is observed providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV.Author SummaryChronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamic of HBV infection and treatment at the molecular level would potentially facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV infection kinetics under interferon-α (IFN) in this model system have not been determined in sufficient detail to support the in-depth studies of HBV treatment response needed to identify/confirm more effective drug targets. In this study 39 chronic HBV-infected uPA/SCID humanized mice treated with IFN and/or lamivudine were analysed using a mathematical modelling approach. We found that IFN main mode of action is blocking HBV DNA synthesis and that 73% of synthesized HBV DNA per are secreted from infected cells. Our data-driven mathematical modeling study provides novel insights into IFN anti-HBV mechanism(s) and viral-host interplay at the molecular level.

scholarly journals Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

2021 ◽  
Author(s):  
Vladimir Reinharz ◽  
Yuji Ishida ◽  
Masataka Tsuge ◽  
Karina Durso-Cain ◽  
Tje Lin Chung ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Adaptive Immune Response ◽  
Pegylated Interferon ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Interferon Α ◽  
B Virus

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during 14-day pegylated interferon-α-2a (pegIFN), LAM or pegIFN+LAM treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the 1st phase represents inhibition of intracellular HBV DNA synthesis and secretion which was similar under all treatments with overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN + LAM (1.28/d) and the slowest (0.1/d) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production, but rather enhanced 2nd phase decline providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV. Importance Chronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamics of HBV infection and treatment response at the molecular level could facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV inhibition kinetics under pegylated interferon-α (pegIFN) in this model system have not been determined in sufficient detail. In this study, viral kinetics in 39 humanized mice treated with pegIFN and/or lamivudine were monitored and analyzed using a mathematical-modelling approach. We found that the main mode of action of interferon-α is blocking HBV DNA synthesis and that the majority of synthesized HBV DNA is secreted. Our study provides novel insights into HBV DNA dynamics within infected human hepatocytes.

scholarly journals Endemic hepatitis B virus (HBV) among hospital in-patients in Bangladesh, including evidence of occult infection

2020 ◽  
Author(s):  
Fazle Rabbi Chowdhury ◽  
Anna L McNaughton ◽  
Mohammad Robed Amin ◽  
Lovely Barai ◽  
Mili Rani Saha ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Occult Hepatitis ◽  
Treatment And Prevention ◽  
B Virus ◽  
High Prevalence ◽  
Hospital Patients ◽  
Surface Gene

ABSTRACTBangladesh is one of the world’s top ten burdened countries for viral hepatitis. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of hepatitis B virus (HBV) infection and to identify cases of occult hepatitis B infection (OBI). HBV exposure (anti-HBc) was documented in 72/201 (36%), and active HBV infection in 16/201 (8%), among whom 3 were defined as OBI (defined as detectable HBV DNA but negative HBsAg). Applying a target-enrichment sequencing pipeline to samples with HBV DNA >3.0log10 IU/ml, we obtained deep whole genome sequences for four cases, identifying genotypes A, C and D. Polymorphisms in the surface gene of the OBI case may account for the negative HBsAg status. We identified mutations associated with nucleos(t)ide analogue resistance, although the clinical significance in this cohort is not known. The high prevalence of HBV in this setting highlights the benefits of offering screening in hospital patients and the importance of HBV DNA testing of transfusion products to reduce the risk of transmission. In order to work towards international Sustainable Development Goal targets for HBV elimination, increased investment is required for diagnosis, treatment and prevention in Bangladesh.

scholarly journals Primary Tupaia Javanica Hepatocyte Culture as an In Vitro Model for Human Hepatitis B Virus Infection

2022 ◽  
Vol 22 (3) ◽  
pp. 203-209
Author(s):  
Kemal Fariz Kalista ◽  
Maryati Surya ◽  
Silmi Mariya ◽  
Diah Iskandriati ◽  
Irsan Hasan ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
In Vitro Model ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Primate Research ◽  
Qualitative And Quantitative ◽  
B Virus ◽  
Vitro Model

Background: Hepatitis B virus (HBV) infection is still one of the biggest health problems in the world, which could lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Treatment for HBV infection has not yet achieved a functional cure. More studies are needed to investigate human HBV (HuHBV), but the scarcity of animal models for HuHBV infection became a barrier. Recently, many studies have shown that Tupaia are suitable for the study of HuHBV. The purpose of this study was to develop a primary tupaia hepatocyte (PTH) culture from T. javanica, a species of Tupaia found in Indonesia, and to prove that HuHBV can replicate in the PTH.Method: In vitro experimental study using PTH isolated from five wild adult T. javanica in Primate Research Center, IPB University. HuHBV was taken from humans with HBsAg and HBV-DNA (+). PTH cells then were infected with HuHBV after reaching 80% confluence. Observation on PTH cells was done everyday for 20 days. Qualitative and quantitative HBsAg were measured using a CMIA while HBV-DNA and cccDNA were measured by RT-PCR.Results: A cytopathic effect was seen on day post infection (DPI)-16. HBsAg and HBV-DNA were detected from DPI-2 until DPI-18, with HBV-DNA level peaked on DPI-12. cccDNA concentration was fluctuating from DPI-2 until DPI-20 with highest level on DPI-16.Conclusion: HuHBV could infect and replicate in PTH from T. javanica can be infected with HuHBV and HuHBV can replicate in the PTH from T. javanica.

The risk of hepatitis B virus infection by transfusion in Kumasi, Ghana

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2419-2425 ◽  
Author(s):  
Jean-Pierre Allain ◽  
Daniel Candotti ◽  
Kate Soldan ◽  
Francis Sarkodie ◽  
Bruce Phelps ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Blood Donors ◽  
Hepatitis B Surface Antigen ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Sub Saharan Africa ◽  
B Virus ◽  
Sub Saharan ◽  
Hbv Transmission

The risk of hepatitis B virus (HBV) transmission by transfusion in sub-Saharan Africa is considered to be relatively low, and testing of blood donors is often not done or is done relatively poorly. To re-examine this attitude, we identified HBV chronically infected blood donors from a major hospital in Ghana with a range of hepatitis B surface antigen (HBsAg) assays. Test efficacy was estimated using HBV DNA as a gold standard, and the risk of HBV infection in blood recipients was estimated for different testing strategies. Particle agglutination, dipstick, and enzyme immunoassay (EIA) HBsAg screening detected 54%, 71%, and 97% of HBV infectious donors, respectively. The risk of HBV transmission to recipients less than 10 years old ranged between 1:11 and 1:326 with blood unscreened and screened by EIA, respectively. For older recipients, the risk decreased a further 4-fold because of the high frequency of natural exposure to HBV. A total of 98% of HBsAg-confirmed positive samples contained HBV DNA. HBV DNA load was less than 1 × 104 IU/mL in 75% of HBsAg-reactive samples, most of them anti-HBe reactive. Approximately 0.5% of HBsAg-negative but anti-HBc-positive samples contained HBV DNA. The use of sensitive HBsAg tests is critical to prevent transfusion transmission of HBV infection to young children in a population with a 15% prevalence of chronic HBV infection in blood donors. However, this will not have much effect on the prevalence of this infection unless other strategies to protect children from infection are also advanced in parallel.

Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

1994 ◽  
Vol 5 (2) ◽  
pp. 57-63 ◽  
Author(s):  
T. Yokota ◽  
K. Konno ◽  
S. Shigeta ◽  
A. Holy ◽  
J. Balzarini ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Hbv Dna ◽  
Inhibitory Effects ◽  
B Virus ◽  
Acyclic Nucleoside ◽  
Cellular Dna ◽  
Acyclic Nucleoside Phosphonate

By using an assay system based on a human hepatoblastoma cell line (HB611) that continuously synthesizes hepatitis B virus (HBV) DNA, 56 acyclic nucleoside phosphonate analogues were examined for their inhibitory effects on HBV DNA synthesis. The following compounds were found to inhibit HBV DNA synthesis at concentrations that were significantly lower than their minimum cytotoxic concentrations; 9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxyethyl) guanine(PMEG), 9-(2-phosphonylmethoxyethyl) guanine ethyl ester (PMEGEE), 9 - (2 - phosphonylmethoxyethyl) - 1 - deazaadenine (PMEC1A), 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), ( S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), 9-(3-isopropoxy-2-phosphonylmethoxypropyl)adenine (IPPMPA), 9-( RS)-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(3-hydroxy-2-phosphonylmethoxypropyl)-2, 6-diaminopurine (HPMPDAP). The most selective compounds (with indexes greater than 100) were PMEDAP, PMEA, IPPMPA, and PMPA. Acyclic pyrimidine nucleoside phosphonate analogues did not prove markedly selective as anti-HBV agents. Diphosphoryl derivatives of some acyclic purine nucleoside phos-phonates (i.e. PMEA, PMEDAP, HPMPA) were prepared. They proved inhibitory to HBV DNA polymerase but not cellular DNA polymerase α.

A new method of concentrating hepatitis B virus (HBV) DNA and HBV surface antigen: an application of the method to the detection of occult HBV infection

Vox Sanguinis ◽  
2008 ◽  
Vol 95 (3) ◽  
pp. 174-180 ◽  
Author(s):  
K. Satoh ◽  
A. Iwata-Takakura ◽  
A. Yoshikawa ◽  
Y. Gotanda ◽  
T. Tanaka ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Surface Antigen ◽  
Hbv Dna ◽  
Hbv Infection ◽  
New Method ◽  
Occult Hbv Infection ◽  
Occult Hbv ◽  
B Virus

scholarly journals Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc–positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study

2016 ◽  
Vol 43 (5) ◽  
pp. 869-874 ◽  
Author(s):  
Valentina Varisco ◽  
Mauro Viganò ◽  
Alberto Batticciotto ◽  
Pietro Lampertico ◽  
Antonio Marchesoni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Core Antigen ◽  
Hbv Reactivation ◽  
Serum Hbsag ◽  
B Virus

Objective.Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc–positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis.Methods.Thirty-three HBsAg-negative/anti-HBc–positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1–8) over 34 months (range 0–80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated.Results.None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs–negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0–70) after RTX discontinuation, no HBV reactivation was observed.Conclusion.The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

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