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Jaroszewicz J.,Hannover Medical School | Jaroszewicz J.,Medical University of Bialystok | Jaroszewicz J.,German Center for Infectious Disease Research | Reiberger T.,Medical University of Vienna | And 21 more authors.
PLoS ONE | Year: 2012

HBsAg clearance is associated with clinical cure of chronic hepatitis B virus (HBV) infection. Quantification of HBsAg may help to predict HBsAg clearance during the natural course of HBV infection and during antiviral therapy. Most studies investigating quantitative HBsAg were performed in HBV mono-infected patients. However, the immune status is considered to be important for HBsAg decline and subsequent HBsAg loss. HIV co-infection unfavorably influences the course of chronic hepatitis B. In this cross-sectional study we investigated quantitative HBsAg in 173 HBV/HIV co-infected patients from 6 centers and evaluated the importance of immunodeficiency and antiretroviral therapy. We also compared 46 untreated HIV/HBV infected patients with 46 well-matched HBV mono-infected patients. HBsAg levels correlated with CD4 T-cell count and were higher in patients with more advanced HIV CDC stage. Patients on combination antiretroviral therapy (cART) including nucleos(t)ide analogues active against HBV demonstrated significant lower HBsAg levels compared to untreated patients. Importantly, HBsAg levels were significantly lower in patients who had a stronger increase between nadir CD4 and current CD4 T-cell count during cART. Untreated HIV/HBV patients demonstrated higher HBsAg levels than HBV mono-infected patients despite similar HBV DNA levels. In conclusion, HBsAg decline is dependent on an effective immune status. Restoration of CD4 T-cells during treatment with cART including nucleos(t)ide analogues seems to be important for HBsAg decrease and subsequent HBsAg loss. © 2012 Jaroszewicz et al. Source


Todt D.,Institute of Experimental Virology | Gisa A.,Hannover Medical School | Radonic A.,Robert Koch Institute | Nitsche A.,Robert Koch Institute | And 14 more authors.
Gut | Year: 2016

Objective Hepatitis E virus (HEV) infection can take chronic courses in immunocompromised patients potentially leading to liver cirrhosis and liver failure. Ribavirin (RBV) is currently the only treatment option for many patients, but treatment failure can occur which has been associated with the appearance of a distinct HEV polymerase mutant (G1634R). Here, we performed a detailed analysis of HEV viral intrahost evolution during chronic hepatitis E infections. Design Illumina deep sequencing was performed for the detection of intrahost variation in the HEV genome of chronically infected patients. Novel polymerase mutants were investigated in vitro using state-of-the-art HEV cell culture models. Results Together, these data revealed that (1) viral diversity differed markedly between patients but did not show major intraindividual short-term variations in untreated patients with chronic hepatitis E, (2) RBV therapy was associated with an increase in viral heterogeneity which was reversible when treatment was stopped, (3) the G1634R mutant was detectable as a minor population prior to therapy in patients who subsequently failed to achieve a sustained virological response to RBV therapy and (4) in addition to G1634R further dominant variants in the polymerase region emerged, impacting HEV replication efficiency in vitro. Conclusions In summary, this first investigation of intrahost HEV population evolution indicates that RBV causes HEV mutagenesis in treated patients and that an emergence of distinct mutants within the viral population occurs during RBV therapy. We also suggest that next-generation sequencing could be useful to guide personalised antiviral strategies. © 2016 BMJ Publishing Group Ltd & British Society of Gastroenterology. Source


Wiegand S.B.,Hannover Medical School | Wiegand S.B.,German Center for Infectious Disease Research | Jaroszewicz J.,Hannover Medical School | Jaroszewicz J.,Medical University of Bialystok | And 10 more authors.
Clinical Microbiology and Infection | Year: 2015

Different viral dominance patterns have been documented in coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) based on HBV DNA and HCV RNA quantification. In most cases, HCV is dominant and suppresses HBV replication. In vitro studies revealed that there is most probably no direct interference between HBV and HCV replication. We hypothesized that indirect mechanisms mediated by host immune responses might be responsible for the different dominance patterns. In this study we analysed quantitative hepatitis B surface antigen (HBsAg) as a marker for immune control of HBV and interferon γ-induced protein 10 (IP-10) as host marker for the endogenous interferon in 85 patients with HBV/HCV coinfection. Levels of HBsAg were closely associated with viral dominance patterns in 85 HBV/HCV-coinfected patients. HBsAg levels were lowest in patients with HCV dominance, even lower compared with HBV-monoinfected patients undergoing treatment with nucleos(t)ide analogues (NA) but comparable to low replicative HBsAg carriers. An increase in HCV RNA during follow up was associated with HBsAg decline. Patients with HCV dominance had significantly higher serum IP-10 levels compared with HBV-dominant patients or HBV-monoinfected patients treated with NA. Lower HBsAg and higher IP-10 levels in HCV-dominant HBV/HCV-coinfected patients suggest that HCV suppresses HBV DNA replication and also HBsAg production by immune mechanisms. © 2015. Source

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