Course Of Hepatitis Research Articles

Liver pathology of hepatitis C, beyond grading and staging of the disease.

Liver biopsy evaluation plays a critical role in management of patients with viral hepatitis C. In patients with acute viral hepatitis, a liver biopsy, though uncommonly performed, helps to rule out other non-viral causes of deranged liver function. In chronic viral hepatitis C, it is considered the gold standard in assessment of the degree of necroinflammation and the stage of fibrosis, to help guide treatment and determine prognosis. It also helps rule out any concomitant diseases such as steatohepatitis, hemochromatosis or others. In patients with chronic progressive liver disease with cirrhosis and dominant nodules, a targeted liver biopsy is helpful in differentiating a regenerative nodule from dysplastic nodule or hepatocellular carcinoma. In the setting of transplantation, the liver biopsy helps distinguish recurrent hepatitis C from acute rejection and also is invaluable in the diagnosis of fibrosing cholestatic hepatitis, a rare variant of recurrent hepatitis C. This comprehensive review discusses the entire spectrum of pathologic findings in the course of hepatitis C infection.

ANTIVIRAL TREATMENT OF HEPATITIS C IN SERBIAN PRISON SETTING: MEDICAL TREATMENT OUTCOMES AND PATIENTS' ADHERENCE.

Seroprevlence of chronic hepatitis C viral infection in correctional facilities ranges from 16% to 49%. However, there are only very limited data available on the course of hepatitis C viral infection and outcomes oftreatment with pegylated interferon plus ribavirin in correctional settings. The aim ofthis study was to assess the feasibility and effectiveness of use of pegylated interferon plus ribavirin treatment in the Serbian correctional setting. The study sample consisted of the patients with hepatitis C hospitalized in the Special Hospital for Prisoners in Belgrade (Serbia) during 2007-2013. Health authorities approved treatment for 32 patients out of 76 treatment-naive patients referred to this institution. The patients (N=32) received 180 mcg pegylated interferon alfa-2a once a week plus oral ribavirin in dosage of 800 mg or 1000/1200 mg/day for 24 or 48-week treatment. All patients who completed therapy were assessed at the end of an additional 24-week treatment-free period for a sustained virological response. Sustained virological response was achieved in 53.8% of hepatitis C viral infection genotype I patients and in 73.3% and 66.6% of patients with hepatitis C viral infection genotype 3 and 4, respectively. One patient with mixed genotype (1, 2) did not achieve sustained virological response. The overall safety profile of the treatment regimen was very good. The incidence of influenza-like symptoms and depression were low A serious adverse event was recorded only in 6.4% of patients. The results showed that pegylated interferon alfa-2a plus ribavirin given once a week was well tolerated among prisoners and the regimen had the same adherence and effectiveness as in general population.

Cellular localization and effects of ectopically expressed hepatitis A virus proteins 2B, 2C, 3A and their intermediates 2BC, 3AB and 3ABC.

In the course of hepatitis A virus (HAV) infections, the seven nonstructural proteins and their intermediates are barely detectable. Therefore, little is known about their functions and mechanisms of action. Ectopic expression of the presumably membrane-associated proteins 2B, 2C, 3A and their intermediates 2BC, 3AB and 3ABC allowed the intracellular localization of these proteins and their possible function during the replication cycle of HAV to be investigated. In this study, we used rhesus monkey kidney cells, which are commonly used for cell culture experiments, and human liver cells, which are the natural target cells. We detected specific associations of these proteins with distinct membrane compartments and the cytoskeleton, different morphological alterations of the respective structures, and specific effects on cellular functions. Besides comparable findings in both cell lines used with regard to localization and effects of the proteins examined, we also found distinct differences. The data obtained identify so far undocumented interactions with and effects of the HAV proteins investigated on cellular components, which may reflect unknown aspects of the interaction of HAV with the host cell, for example the modification of the ERGIC (ER-Golgi intermediate compartment) structure, an interaction with lipid droplets and lysosomes, and inhibition of the classical secretory pathway.

Hepatitis B immune status in adolescents vaccinated during infancy: A retrospective cohort study from a pediatric practice in Germany

abstractIn Germany, vaccination of infants against hepatitis B is recommended since 1995. However, data on long-term immunity is sparse and the necessity of a booster dose remains uncertain. Aims of this study were to assess the long-term persistence of antibodies to the hepatitis B surface antigen (anti-HBs) after immunization during infancy and the effect of a subsequent hepatitis B booster vaccination during adolescence on anti-HBs levels. Patients from a private pediatric practice who had received a full vaccination course of hepatitis B as infants and who were quantitatively tested for anti-HBs during adolescence (pre-booster levels) were included. In those participants who received a hepatitis B booster, post-booster anti-HBs levels were measured. Univariate analyses were conducted to determine factors associated with pre- and post-booster anti-HBs levels, respectively. 106 participants (53% male) were included in the study. At an average of 13.7 y after primary vaccination, 14% of participants had an anti-HBs level of ≥100 IU/l, while 46% were at 10–99 IU/l and 40% had anti-HBs levels of <10 IU/l. In total, 34 received a booster vaccination. Of those, 97% (33/34) had post-booster anti-HBs levels ≥ 100 IU/l, which were independent from pre-booster levels. No other patient characteristics were associated with pre-booster or post-booster anti-HBs≥ 100 IU/l. Although almost half of study participants showed low anti-HBs levels at follow-up, robust responses to booster vaccination suggest that adolescents who received the full vaccination course during infancy are still protected against hepatitis B infection.

Clinical course of hepatitis B surface antigen positive subjects following screening: A retrospective observational study from April 2008 to January 2013.

Determination of the percentage of hepatitis B surface antigen (HBsAg) positive participants who undergo screening and treatment may reduce the development of hepatocellular carcinoma. This study assessed the percentages of HBsAg positive participants detected by free screening at medical institutions in Saga Prefecture who underwent detailed examinations and antiviral treatment. Participants were screened for HBsAg positivity at medical institutions in Saga Prefecture from April 2008 to January 2013, with some visiting physicians for detailed examinations and applying for reimbursement. Participants in the database of the Health Promotion Division of Saga Prefecture and results of detailed examinations were analyzed retrospectively. Screening revealed 193 eligible participants, 105 men (54%) and 88 women (46%), of a mean age of 55.5 ± 14.9years. Of these 193 participants, 147 (76%) visited physicians for detailed examinations, 24 (16%) were regarded as needing treatment and seven (3.6%) were reimbursed for antiviral treatments. The 46 participants who did not undergo detailed examinations were significantly younger than the 147 examined participants (50.9 ± 13.2 vs 56.9 ± 15.2years, P = 0.018). Of the 110 participants thought to require observation, 68 (62%) were assigned to this group without determination of alanine aminotransferase or hepatitis B virus DNA concentration, and 15 (14%) had indications for antiviral treatment according to the 2014 guidelines of the Japanese Society of Hepatology. The proportion of HBsAg positive participants receiving antiviral treatment was lower than that of participants undergoing detailed examinations.

Claudin-6 and Occludin Natural Variants Found in a Patient Highly Exposed but Not Infected with Hepatitis C Virus (HCV) Do Not Confer HCV Resistance In Vitro.

The clinical course of Hepatitis C Virus (HCV) infection is highly variable between infected individual hosts: up to 80% of acutely HCV infected patients develop a chronic infection while 20% clear infection spontaneously. Spontaneous clearance of HCV infection can be predicted by several factors, including symptomatic acute infection, favorable IFNL3 polymorphisms and gender. In our study, we explored the possibility that variants in HCV cell entry factors might be involved in resistance to HCV infection. In a same case patient highly exposed but not infected by HCV, we previously identified one mutation in claudin-6 (CLDN6) and a rare variant in occludin (OCLN), two tight junction proteins involved in HCV entry into hepatocytes. Here, we conducted an extensive functional study to characterize the ability of these two natural variants to prevent HCV entry. We used lentiviral vectors to express Wildtype or mutated CLDN6 and OCLN in different cell lines and primary human hepatocytes. HCV infection was then investigated using cell culture produced HCV particles (HCVcc) as well as HCV pseudoparticles (HCVpp) expressing envelope proteins from different genotypes. Our results show that variants of CLDN6 and OCLN expressed separately or in combination did not affect HCV infection nor cell-to-cell transmission. Hence, our study highlights the complexity of HCV resistance mechanisms supporting the fact that this process probably not primarily involves HCV entry factors and that other unknown host factors may be implicated.

Current antiviral practice and course of Hepatitis B virus infection in inflammatory arthritis: a multicentric observational study (A + HBV study)

The reactivation of hepatitis B virus (HBV) infection is a well-known event in hepatitis B surface antigen (HbsAg)-positive patients receiving immunosuppressive therapy. The objective of this study was to assess the antiviral practice and course of HBV infection in inflammatory arthritis. Nineteen rheumatology centers participated in this retrospective study. HbsAg-positive patients who were taking disease-modifying antirheumatic drugs and who were being tested for HBV viral load at a minimum of two different time points were included. The case report form (CRF) consisted of demographic data, rheumatic diseases, treatment profiles, transaminase levels, viral hepatitis serological markers, and HBV viral load. The reactivation of HBV was defined as the abrupt rise in HBV replication by an increase in serum HBV DNA levels in a patient with a previously inactive HBV infection. In total, the data of 101 (female 50.5%) patients were included (76 patients with inactive HBV carriers and 25 patients with chronic HBV infection). The mean age of patients was 44±12 years, and the mean follow-up duration was 31±22 months. Of the 101 patients, 70 (69.3%) received antiviral treatment. HBV reactivation was detected in 13 of 76 (17.1%) patients with inactive HBV carriers. HBV reactivation was observed less frequently, not although significantly, in those patients receiving antiviral prophylaxis compared with those not receiving prophylaxis [5/41 (12.2%) vs. 8/33 (24.2%), p=0.17]. Forty-two patients (31 patients had inactive HBV carriers) were using anti-tumor necrosis factor agents. HBV reactivation was detected in 6 of the 31 (19.3%) patients. Twenty-five patients had chronic hepatitis, and five (20%) of them had not received antiviral prophylaxis. HBV viral loads were persistently elevated in 7 (28%) of 25 patients (three patients under and four patients not under antiviral treatment). HBV reactivation was observed in approximately 17% of patients under immunosuppressive treatments. HBV reactivation was more frequently observed in those who did not receive antiviral prophylaxis.

Decreasing immunity to hepatitis A virus infection among US adults: Findings from the National Health and Nutrition Examination Survey (NHANES), 1999–2012

BackgroundThe clinical course of hepatitis A virus (HAV) infection is more severe with increased age. In the United States, surveillance data reported to CDC since 2011 indicate increases in both the absolute number of cases and the mean age of cases. Total antibody to HAV (anti-HAV) is a marker of immunity. MethodsWe analyzed National Health and Nutrition Examination Survey (NHANES) data for anti-HAV from respondents aged ≥2 years collected from 2007 to 2012 and compared with data collected 10 years earlier (1999–2006). For US-born adults aged ≥20 years, we estimated age-adjusted anti-HAV prevalence by demographic and other characteristics, evaluated factors associated with anti-HAV positivity and examined anti-HAV prevalence by decade of birth. ResultsThe prevalence of anti-HAV among adults aged ≥20 years was 24.2% (95% CI 22.5–25.9) during 2007–2012, a significant decline from 29.5% (95% CI 28.0–31.1) during 1999–2006. Prevalence of anti-HAV was consistently lower in 2007–2012 compared to 1999–2006 by all characteristics examined. In 2007–2012, the lowest age-specific prevalence was among adults aged 30–49 years (16.1–17.6%). Factors significantly associated with anti-HAV positivity among adults were older age, Mexican American ethnicity, living below poverty, less education, and not having insurance. By decade of birth, the prevalence of anti-HAV was slightly lower in 2009–2012 than in 1999–2002, except among persons born from 1980 to 1989. ConclusionsNHANES data document very low prevalence of hepatitis A immunity among U.S. adults aged 30–49 years; waning of anti-HAV over time may be minimal. Improving vaccination coverage among susceptible adults should be considered.

Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis.

In viral hepatitis, inflammation is correlated with chronic oxidative stress, one of the biological events leading to DNA damage and hepatocellular carcinoma (HCC) development. Aim of this study was to investigate the complex molecular network linking oxidative damage to telomere length and telomerase activity and regulation in hepatitis C and B virus-related liver carcinogenesis. We investigated 142 patients: 21 with HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in different stages. We evaluated 8-hydroxydeoxyguanosine (8-OHdG), marker of oxidative DNA damage, OGG1 gene polymorphism, telomere length, telomerase activity, TERT promoter methylation, and mitochondrial TERT localization. In hepatitis C-related damage, 8-OHdG levels increased since the early disease stages, whereas hepatitis B-related liver disease was characterized by a later and sharper 8-OHdG accumulation (P=0.005). In C virus-infected patients, telomeres were shorter (P=0.03), whereas telomerase activity was higher in tumors than that in the less advanced stages of disease in both groups (P=0.0001, P=0.05), with an earlier increase in hepatitis C. Similarly, TERT promoter methylation was higher in tumor and peritumor tissues in both groups (P=0.02, P=0.0001). Finally, TERT was localized in mitochondria in tumor and peritumor samples, with 8-OHdG levels significantly lower in mitochondrial than those in genomic DNA (P=0.0003). These data describe a pathway in which oxidative DNA damage accumulates in correspondence with telomere shortening, telomerase activation, and TERT promoter methylation with a different time course in hepatitis B and C virus-related liver carcinogenesis. Finally, TERT localizes in mitochondria in HCC, where it lacks a canonical function.

Donor- and recipient-derived immunity in ABO incompatible living-related liver transplantation

This report describes how donor- and recipient-derived immunity was influenced by immunosuppressive treatment of ABO incompatibility (rituximab and immunoadsorption/plasmaphereses) in the long-term. We present an 8-year course of Hepatitis B virus (HBV) immunity, isohemagglutinins and B cell numbers. Whereas cellular HBV immunity was transferred from the HBV vaccinated donor (blood group A1) to the HBV naïve recipient (blood group 0), humoral HBV specific immune transfer was lacking. Starting at month 17 after transplantation, the recipient was vaccinated six times against HBV. Anti-HBs did not appear until the sixth vaccination at month 44. Immunoadsorption prior to transplantation reduced anti-A1 IgG titers from 256 to 2. Titers after transplantation remained low (⩽64). B cell numbers were below standard values up to month 26, then normalized and exceeded normal values from year 7 to 8 post transplantation. In conclusion, donor-derived B cell immunity was lost but recipient-derived immunity persisted after ABO incompatible transplantation.

Studies of nosocomial outbreaks of hepatitis B in nursing homes in Germany suggest a major role of hepatitis B e antigen expression in disease severity and progression

Hepatitis B virus (HBV) causes acute or chronic hepatitis B. Local outbreaks of HBV infections in skilled nursing facilities is a matter of growing concern in developed countries. Here, we investigated two outbreaks of hepatitis B that recently occurred in nursing homes in Germany. The outbreak at location A was associated with acute fulminant hepatitis with fatal outcome in several cases, while individuals infected at location B developed asymptomatic or mild hepatitis B. Sequence analysis of viruses involved in these outbreaks revealed different, but unique HBV strains for each location. Each of the strains produced high viremia of more than 109 virions/mL serum. We found that the mild course of hepatitis B at location B was caused by a circulating wild-type HBV genotype A2 strain, which is commonly found in Central Europe. Complete genome sequences of isolates obtained from infected patients revealed nearly 100% sequence identity at the nucleotide level as well as expression of HBV e protein (HBeAg), a known T cell tolerogen in the incubation or chronic phases of HBV infection. By contrast, the outbreak at location A was associated with an HBV genotype D2 variant that lacked HBeAg expression, suggesting that immunopathology and selection of specific HBV variants played a major role in the severe (or even fulminant) acute hepatitis observed at location A. Importantly, all patients were diagnosed with type 2 diabetes mellitus, a known risk factor for healthcare-associated transmission of HBV. The study leads us to suggest that, besides strict adherence to hygiene standards, additional efforts are required to reduce the risk of HBV transmission and fulminant disease progression in healthcare settings and nursing homes. In this context, a general screening for HBsAg and active hepatitis B vaccination should be considered for people living in nursing homes, especially for those with diagnosed diabetes or other predisposing factors for HBV transmission.

Hepatocellular Carcinoma in Patients with a Sustained Response to Anti-Hepatitis C Therapy.

Hepatocellular carcinoma (HCC) is a common, life-threatening complication of longstanding infection with the hepatitis C virus (HCV), likely a consequence of the direct oncogenic activity of the virus cooperating with liver cell inflammation in transforming the liver into a mitogenic and mutagenic environment. The achievement of a sustained virological response (SVR) to interferon-based therapies has been shown to benefit the course of hepatitis C in terms of reduced rates of liver-related complications and mortality from all causes. Interestingly, while achievement of an SVR is associated with a negligible risk of developing clinical decompensation over the years, the risk of HCC is not fully abrogated following HCV clearance, but it remains the dominant complication in all SVR populations. The factors accounting for such a residual risk of HCC in SVR patients are not fully understood, yet the persistence of the subverted architecture of the liver, diabetes and alcohol abuse are likely culprits. In the end, the risk of developing an HCC in SVR patients is attenuated by 75% compared to non-responders or untreated patients, whereas responders who develop an HCC may be stratified in different categories of HCC risk by a score based on the same demographic and liver disease-based variables, such as those that predict liver cancer in viremic patients. All in all, this prevents full understanding of those factors that drive HCC risk once HCV has been eradicated. Here, we critically review current understanding of HCC in SVR patients focusing on factors that predict residual risk of HCC among these patients and providing a glimpse of the expected benefits of new anti-HCV regimens based on direct antiviral agents.

Host genetic variants influencing the clinical course of hepatitis B virus infection.

The clinical course of hepatitis B virus (HBV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HBV infection. Recent genome-wide association studies identified several host genetic factors influencing the clinical course of HBV infection. Genetic variations in HLA class II loci were significantly associated with susceptibility to persistent HBV infection. Other polymorphisms in or near the genes EHMT2, TCF19, and HLA-C, located near HLA class II loci, and UBE2L3 were also associated with persistent HBV infection. Meanwhile, polymorphisms in KIF1B, GRIK1, and STAT4 were associated with HBV-related hepatocellular carcinoma (HCC). Interestingly, HLA class II genetic variations were strongly associated with not only persistent HBV infection, but also disease progression and HBV-related HCC in chronic hepatitis B. Understanding the various genetic factors associated with the clinical course of HBV infection is essential for personalized treatment and surveillance of disease progression and HCC.

Host genetic variants influencing the clinical course of hepatitis C virus infection.

The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma.

Hepatitis C virus in children

Chronic hepatitis C viral infection represents a worldwide viral epidemic. The natural course of hepatitis C virus is less understood in the pediatric population, although fewer children progress to cirrhosis and end-stage liver disease than adults infected. In the last five years, epidemiological and clinical research involving hepatitis C virus-infected children has raised interesting observations regarding the differences in transmission, natural history, and response to treatment in this population.

Genetic (KIR, HLA-C) and Some Clinical Parameters Influencing the Level of Liver Enzymes and Early Virologic Response in Patients with Chronic Hepatitis C.

Natural killer cells play an important role as effectors of innate immunity and regulators of adaptive immunity. They are important elements of the innate response to viral infections, which they detect using human leukocyte antigen (HLA) class I-binding receptors. Most polymorphic of these are killer cell immunoglobulin-like receptors (KIRs) which exist as two basic isotypes, activating or inhibitory receptors and are encoded by genes distributed differently in unrelated individuals. We searched for links between selected clinical data (including HCV viremia, liver enzymes level and liver histology parameters) and the presence of genes encoding these receptors and their ligands in hepatitis C virus-infected individuals subjected to pegylated interferon-α and ribavirin therapy. Genomic DNA samples from two hundred and ninety-two chronically infected patients were typed by polymerase chain reaction for the presence or absence of genes for KIRs and their ligands, class I HLA molecules, and clinical data of the patients were collected. Our results suggest an importance of clinical parameters and the contribution of KIR and HLA genes to the course of hepatitis C virus infection and the response to therapy. The study revealed that levels of liver enzymes before therapy were about 30 % higher in patients who possessed a variant KIR2DS4 gene with 22-base pair deletion. Decrease of ALT activity after treatment was higher in HLA-C C2-positive than negative individuals. Beside it, patients demonstrated early virologic response to the therapy if the time lag before treatment was short, particularly in women.

NOD1 ligand modulates the course of hepatitis B virus infection in hydrodynamic injection mouse model

NOD1 ligand modulates the course of hepatitis B virus infection in hydrodynamic injection mouse model

Relevance of chronic hepatitis E in liver transplant recipients: a real-life setting.

The chronic course of hepatitis E virus (HEV) infections in orthotopic liver transplant (OLT) recipients has been described previously, but prospectively collected data are rare. We aimed to study the role of chronic hepatitis E in OLT in a real-life setting. Therefore, 287 adult OLT recipients (169 male [59%], median age 56 years) were prospectively tested by HEV polymerase chain reaction assay (lower level of detection = 10 IU/mL), irrespective of their level of liver enzymes. In 4 patients (1.4%), chronic HEV infection was diagnosed. All 4 patients were male, and their age (median 48.5 years), the time since transplantation (median 45.5 months), and bilirubin level (median 0.6 mg/dL) did not differ significantly from the total cohort. However, alanine transaminase and aspartame transaminase levels were significantly higher in HEV-infected patients (75-646 U/L, median 216 U/L and 68-317 U/L, median 108 U/L) than in non-infected patients (6-617 U/L, median 41 and 6-355 U/L, median 36; P = 0.004 and 0.040, Mann-Whitney test). In 3 patients, liver biopsy was performed and revealed signs of inflammation and chronic liver disease, as enlarged densely infiltrated portal tracts with mild-to-moderate interface hepatitis. All infected patients were treated with ribavirin with the starting dose adjusted to renal function (400-800 mg/day). In 2 patients, dose reduction was necessary. Transaminases normalized in all 4 patients, and all patients cleared their infection within 3 months of ribavirin treatment. However, 1 patient experienced viral relapse 12 weeks after discontinuation. Ribavirin medication was re-started and viral clearance occurred within 8 weeks and persisted. Sequence analysis of the HEV genome of this patient revealed that he was infected with an HEV variant, which recently has been shown to have a reduced response to ribavirin in cell culture. The risk of chronic HEV infections in OLT recipients in low-endemic countries should not be overestimated. No case of chronic hepatitis E was observed in patients with normal liver enzymes, indicating that general screening of all OLT recipients is not necessary. However, if chronic hepatitis E develops, it can be treated efficiently with ribavirin.

Tenofovir discontinuation after long-term viral suppression in HBeAg negative chronic hepatitis B. Can HBsAg levels be useful?

BackgroundRecent studies have shown that antiviral treatment discontinuation is safe and associated with virologic remission in HBeAg-negative patients. However, the period of viral suppression and follow-up in these studies was relatively short. ObjectivesTo investigate whether continuous viral suppression with tenofovir disoproxil fumarate for more than 7 years is associated with HBsAg loss and sustained response after treatment discontinuation and receiving a full course of hepatitis B vaccination. Study designPatients with HBeAg-negative chronic HBV infection and more than 7 years of persistent viral suppression with tenofovir therapy were selected for treatment discontinuation and HBV vaccination. Follow-up with monthly ALT, HBV–DNA, and HBsAg determinations lasted 72 weeks. In patients with viral relapse, the viral quasispecies in the overlapping reverse transcriptase and small surface protein regions was analysed by ultra-deep pyrosequencing. ResultsEight of 17 HBeAg-negative patients accepted tenofovir discontinuation: 5 patients achieved sustained response (persistent HBV–DNA levels <2000IU/mL and normal ALT) despite an initial virologic relapse, one lost HBsAg, and two needed re-treatment. All patients with an on-treatment HBsAg level decline >5000IU/mL achieved sustained response. Patients with HBsAg level <100IU/mL during an ALT flare after antiviral discontinuation achieved sustained response. Significant changes were seen in the composition of the HBV quasispecies, and half the patients showed changes in HBV genotype. ConclusionsEven though the majority of patients presented an initial relapse with selection of HBV variants, most achieved sustained response. Changes in HBsAg levels on and off treatment may be useful for predicting the likelihood of virologic remission.

Hepatitis C virus attenuates mitochondrial lipid β-oxidation by downregulating mitochondrial trifunctional-protein expression.

ABSTRACTThe course of hepatitis C virus (HCV) infection and disease progression involves alterations in lipid metabolism, leading to symptoms such as hypocholesterolemia and steatosis. Steatosis can be induced by multiple mechanisms, including increases in lipid biosynthesis and uptake, impaired lipoprotein secretion, and/or attenuation of lipid β-oxidation. However, little is known about the effects of HCV on lipid β-oxidation. A previous proteomics study revealed that HCV interacted with both the α- and β-subunits of the mitochondrial trifunctional protein (MTP), an enzyme complex which catalyzes the last 3 steps of mitochondrial lipid β-oxidation for cellular energy production. Here we show that in HCV-infected Huh7.5 cells, lipid β-oxidation was significantly attenuated. Consistently with this, MTP protein and mRNA levels were suppressed by HCV infection. A loss-of-function study showed that MTP depletion rendered cells less responsive to alpha interferon (IFN-α) treatment by impairing IFN-stimulated gene expression. These aspects of host-virus interaction explain how HCV alters host energy homeostasis and how it may also contribute to the establishment of persistent infection in the liver.IMPORTANCE HCV infection triggers metabolic alterations, which lead to significant disease outcomes, such as fatty liver (steatosis). This study revealed that HCV impairs mitochondrial lipid β-oxidation, which results in low lipid combustion. On the other hand, the HCV-induced defects in metabolic status played an important role in the control of the type I interferon system. Under the conditions of impaired lipid β-oxidation, host cells were less responsive to the ability of exogenously added IFN-α to suppress HCV replication. This suggests that interference with lipid β-oxidation may assist the virus in the establishment of a long-term, persistent infection. Further understanding of this aspect of virus-host interaction may lead to improvements in the current standard therapy.