Long-term Hepatitis Research Articles

The duration of hepatitis B vaccine immunity in pediatric dialysis patients.

Dialysis patients are at risk for hepatitis B infection, a serious but preventable disease. Long-term hepatitis B protection has not been defined in pediatric patients with chronic kidney disease stage 5 on dialysis (CKD 5D) who were vaccinated as infants or children. Annual hepatitis B antibody surveillance data were collected retrospectively on a cohort of pediatric CKD 5D patients (n = 202) at a single institution and analyzed by survival analysis to assess hepatitis B immunity duration. Median duration of immunity by Kaplan-Meier analysis since primary vaccination was 106.3 [95 % confidence interval (CI) 93.9, 124.4] months. After the initiation of dialysis, the median duration of hepatitis B immunity was 37.1 (95 % CI 24.2, 72.3) months. Multivariate adjusted analysis showed that there was a significant difference in the duration of hepatitis immunity based on the timing of hepatitis B vaccination (p < 0.001). Patients immunized after starting dialysis had a hazard ratio of 6.13 (95 % CI 2.87, 13.08) for hepatitis B immunity loss compared to patients immunized as infants (p < 0.001). After dialysis initiation, protective hepatitis B antibody levels wane rapidly, with a shortened duration of immunity. In our cohort of pediatric patients with CKD 5D, this decline was more pronounced in children who were immunized after starting dialysis than in those who received hepatitis B immunizations during childhood. Both groups of patients should be monitored with serial antibody titers.

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients.

To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients. We retrospectively compared the liver biopsies of well-matched HCV LT recipients under calcineurin inhibitors (CNI group, n = 21) and mycophenolate (MMF group, n = 15) monotherapy, with those patients who successfully withdrawn immunosuppression (IS) therapy from at least 3 years (TOL group, n = 10). To perform the well-matched analysis, all HCV transplanted patients from December 1993 were screened. Only those HCV patients who reached the following criteria were considered for the analysis: (1) at least 3 years of post-operative follow-up; (2) patients with normal liver graft function under low dose CNI monotherapy (CNI group); (3) patients with normal liver graft function under antimetabolite (Micophenolate Mofetil or coated mycophenolate sodium) monotherapy (MMF group); and (4) recipients with normal liver function without any IS. We excluded from the analysis recipients who were IS free or under monotherapy for < 36 mo, recipients with cirrhosis or with unstable liver function tests. Thirty six recipients were enrolled in the study. Demographics, clinical data, time after LT and baseline liver biopsies were comparable in the three groups. After six years of follow-up, there was no worsening of hepatic fibrosis in the MMF group (2.5 ± 1.5 Ishak Units vs 2.9 ± 1.7 Ishak Units, P = 0.5) and TOL group (2.7 ± 10.7 vs 2.5 ± 1.2, P = 0.2). In contrast, a significant increase in the fibrosis score was observed in the CNI group (2.2 ± 1.7 vs 3.9 ± 1.6, P = 0.008). The yearly fibrosis progression rate was significantly worse in the CNI group (0.32 ± 0.35) vs MMF group (0.03 ± 0.31, P = 0.03), and TOL group (-0.02 ± 0.27, P = 0.02). No differences have been reported in grading scores for CNI group (2.79 ± 1.9, P = 0.7), MMF group (3.2 ± 1.5, P = 0.9) and TOL group (3.1 ± 1.4, P = 0.2). Twenty four patients were treated with low dose ribavirin (8 TOL, 7 MMF, 9 CNI). The hepatitis C titers were comparable in the three groups. No episodes of rejection have been reported despite differences of liver function test in the three groups during the observational period. IS withdrawal and MMF monotherapy is safe and seems to be associated with the slowest fibrosis progression in HCV LT recipients.

High Titre Anti HBs Human Plasma (or) Hyper Immune Plasma (HIP): A Cost Effective Management of HBV Recurrence in Post Liver Transplant Recipients: A Preliminary Observation

Background: Prophylaxis with long-term hepatitis B immunoglobulin (HBIG) and nucleoside analogous can prevent HBV recurrence in liver transplant (LT) recipients. HBIG dose is adjusted to maintain anti HBsAb level to >100 IU/mL. A single dose of HBIG (1000 IU) per month costs Rs 50,000/-.

Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely

Information regarding long-term HBsAg kinetics during treatment with nucleoside/nucleotide analogues is limited. The aim of the present study was to assess whether finite nucleoside/nucleotide analogue treatment duration could be envisaged during the patient's lifetime. Patients with chronic hepatitis B receiving different schedules of nucleoside/nucleotide analogues were followed for a median duration of 102 months, i.e., 8.5 years (interquartile range: 88-119 months). Long-term HBV DNA and HBsAg level kinetics were modeled in order to estimate time to clear HBsAg during therapy in patients with undetectable HBV DNA. Antiviral therapy was associated with a slow but consistent reduction in the level of HBsAg in most of the patients. Three patterns of HBsAg level declines were identified: decline during both the detectable and undetectable HBV DNA phases; decline during the HBV DNA detectable period only; decline during the HBV DNA undetectable period only. The mean HBsAg titer at the time when HBV DNA became undetectable was 3.29 ± 0.49 Log₁₀ international units (IU)/ml, and the mean slope was -0.007 ± 0.007 Log₁₀ IU/month, i.e., an average decline of 0.084 Log₁₀ IU/year. The corresponding calculated median number of years needed to clear HBsAg was 52.2 years (interquartile range: 30.8-142.7). This study, based on the very long-term follow-up of patients with chronic hepatitis B treated with potent nucleoside/nucleotide analogues, shows that HBsAg clearance is unlikely to occur during the patient's lifetime, even if HBV replication is well controlled. Thus, lifetime therapy is required in the vast majority of HBV-infected patients.

DDB1 is a cellular substrate of NS3/4A protease and required for hepatitis C virus replication

Hepatitis C virus (HCV) infection often causes long-term persistent hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma. HCV-encoded NS3/4A protease plays an important role in HCV immune evasion by cleaving key adapter proteins VISA and TRIF of the RIG-I-like receptors and Toll-like receptors mediated interferon (IFN) induction pathways. To further understand the roles of NS3/4A in HCV life cycle, we identified DDB1 as a cellular substrate of NS3/4A protease by biochemical purification and mass spectrometry analysis. NS3/4A interacted with DDB1 and cleaved DDB1 in HCV-infected cells. Mutagenesis indicated that NS3/4A cleaved DDB1 at the residue of C378. Overexpression of DDB1 potentiated HCV replication, whereas knockdown of DDB1 dramatically inhibited HCV replication. Furthermore, our data indicated that the cleavage of DDB1 by NS3/4A protease was required for HCV replication. Our findings suggest that DDB1 is a cellular substrate of NS3/4A required for HCV replication and provide new insight into the interaction between HCV and host cells.

Factors influencing long-term hepatitis B virus infection of the tree shrew (Tupaia belangeri chinensis) as an in vivo model of chronic hepatitis B

To determine the methods for establishing an in vivo model of long-term hepatitis B virus (HBV) infection in the Chinese tree shrew (Tupaia belangeri chinensis). Seventy-seven neonate (1-3 days old) and 49 young adult (2 weeks to 1 year old) tree shrews were inoculated with different HBV sources (chronic hepatitis B (CHB) human patient serum, single or pooled; HBV-infected tree shrew serum, single only; HBV-infected HepG2.2.15 cells' culture medium supernatant; HBV genome-transfected HepG2.2.15 cells' culture medium supernatant) through various routes of injection (subcutaneous, intraperitoneal, and direct liver via abdominal skin; adults also received intravenous and indirect liver via spleen). Serum and liver biopsies were collected from the animals at various time points post-inoculation for detection of HBV markers by fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, time-resolved immunofluorescence, Southern blotting, dot blotting, immunohistochemistry, and microscopy. Among the neonatal group of tree shrews, six (7.8%) were confirmed as HBV-infected for more than 72 (up to 228) weeks after inoculation and another seven (9.1%) were suspected of persistent infections. None of the young adult tree shrews developed persistent infection. Inoculation with single-source serum from either CHB humans or tree shrews were responsible for the most cases of infections, and the subcutaneous injection produced more infections than the other inoculation routes. The most reliable methods of determining HBV infection status were detection of serum HBV immunoreactive markers and intrahepatic HBV DNA. In order to establish an in vivo model of CHB in the tree shrew, the animals should be inoculated in the neonatal period using subcutaneous injection.

Long-Term Hepatitis B Virus (HBV) Response to Lamivudine-Containing Highly Active Antiretroviral Therapy in HIV-HBV Co-Infected Patients in Thailand

BackgroundApproximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known.Methodology/Principal FindingHIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 log10 IU/mL and 4.47 log10 copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L.ConclusionsAll HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC.

Elevated liver enzymes resulting from an interaction between Raltegravir and Panax ginseng: a case report and brief review

In the last decade, some evidence has arisen supporting the usefulness of Asian ginseng (Panax ginseng, fam. Araliaceae) as a complementary remedy in patients receiving antiretroviral therapy. However, its role in current therapeutics remains unclear. The patient was admitted for an acute elevation of liver enzymes, marked jaundice, and significant weight loss after taking ginseng-based tablets starting approximately 39 days prior. His past medical history (PMH) was also significant for HIV+, long-term hepatitis C, an episode of mitochondrial toxicity, and several comorbidities. His outpatient medications included raltegravir 400 mg plus lopinavir/ritonavir 400/100 mg twice daily, aspirin 100 mg daily, and esomeprazole 40 mg daily as needed. The cessation of the ginseng lozenges led to a progressive improvement in the performance status and laboratory values. Both the Hansten and Horn nomogram and the Roussel Uclaf Causality Assessment Method indicated that the association between the ginseng medicine and the liver injury was probable (six points). We suggest that ginseng is involved in the episode through an interaction resulting in elevated plasma concentrations of raltegravir. As a consequence, clinicians should be alert when managing patients on other CYP3A4-metabolized drugs or previous liver-damaging conditions. However, larger studies are required to explicitly clarify these statements.

Venous access and care: harnessing pragmatics in harm reduction for people who inject drugs

To explore the facilitators of long-term hepatitis C avoidance among people who inject drugs. We employed a qualitative life history design. Recruitment took place through low-threshold drug services and drug user networks in South East and North London. Participants were interviewed at the recruitment services or in their homes. The sample comprised 35 people who inject drugs, 20 of whom were hepatitis C antibody-negative. Participants' average injecting trajectory was 19 years (6-33), with 66% primarily injecting heroin, and 34% a crack and heroin mix. Nine (26%) of the sample were female and the average age was 39 years (23-53). Two interviews were conducted with each participant, with the second interview incorporating reference to a computer-constructed life history time-line. Interview accounts were audiorecorded, transcribed verbatim and analysed thematically. Hepatitis C risk awareness was recent and deprioritized by the majority of participants. The facilitation of venous access and care was an initial and enduring rationale for safe injecting practices. Difficult venous access resulted in increased contamination of injecting environments and transitions to femoral injecting. Participants expressed an unmet desire for non-judgemental venous access information and advice. Harm reduction interventions which attend to the immediate priorities of people who inject drugs, such as venous access and care, have the potential to re-engage individuals who are jaded or confused by hepatitis C prevention messages.

Universal Hepatitis B Vaccination Reduces Childhood Hepatitis B Virus–Associated Membranous Nephropathy

To compare the incidence of hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) before and after universal HBV vaccination and to identify factors underlying the change. This study included 471 hospitalized children with nephrotic syndrome (NS) and 488 long-term follow-up hepatitis B surface antigen (HBsAg)-carrier children. Horizontal transmission (negative maternal HBsAg status) of HBVMN and HBV was assessed, and the incidence of HBVMN was compared before and after initiation of the universal HBV vaccination program started in 1984. The frequency of HBVMN in children with NS was 11.6% between 1974 and 1984, 4.5% between 1984 and 1994, 2.1% between 1994 and 2004, and 0% between 2004 and 2009. Similarly, the number of HBsAg-seropositive children with NS (mainly via horizontal infection) decreased after universal vaccination. The prevaccination frequency of HBV horizontal transmission in chronic HBsAg carriers from the general population was 36.5% compared with 5% in the postvaccination period. The incidence of HBVMN in these carriers revealed a parallel decline. Our results revealed a significant decrease in the frequency of HBVMN in children with NS and in long-term follow-up HBsAg carriers. Children with HBVMN are primarily infected with HBV via horizontal transmission; thus, the significant reduction in horizontal transmission in HBsAg-carrier children in the general population after universal HBV vaccination may explain the reduction of HBVMN in the vaccinated population. These findings confirm the effectiveness of HBV vaccination on reducing the incidence of HBVMN, possibly through a significant decline in horizontal HBV infection.

Prevention of Hepatitis B Recurrence in Liver Transplant Patients Using Oral Antiviral Therapy without Long-Term Hepatitis B Immunoglobulin

: Background: Small studies have suggested that nucleos(t)ide analogue therapy (NAT) with reduced hepatitis B immunoglobulin (HBIG) duration may be efficacious in preventing post-liver transplantation (LT) HBV recurrence. Objectives:This larger study evaluates the use of NAT with short term (< 6 mo) or no HBIG for prevention of post-LT HBV recurrence.Patients and Methods: All HBV patients undergoing LT at a university transplant center between 2002 and 2007 were identified retrospectively. Patient demographics, medication regimen, and adverse events were noted. The primary endpoint was HBV recurrence and secondary endpoints were graft and patient survival. Results: 28 study patients were identified. Of these 28 patients, 4 (14%) received no HBIG, 6 (22%) received only inpatient HBIG, and 18 (64%) received inpatient HBIG and outpatient HBIG. 16 of the 28 patients (57%) received combination NAT and 12 patients (43%) received single NAT. At a median time of 15.5 months (range 9-24 months) post-LT, 4 of the 28 patients (14%) had recurrent HBV. Of those patients with recurrent HBV, 3 received both inpatient and outpatient HBIG and 1 received no HBIG. All cases of HBV recurrence were associated with noncompliance. Conclusions: NAT with short-term or no HBIG was efficacious and safe in preventing post-LT HBV. All compliant patients were HBV-free, including 9 patients who received no HBIG or only inpatient HBIG. Additional studies using NAT without HBIG appear justified. Keywords: Hepatitis B; Liver transplantation; Immunoglobulin Implication for health policy/practice/research/medical education:Hepatitis B viral infection is a worldwide problem affecting 400 million people. The advent of hepatitis B immunoglobulin and antiviral therapy has reduced the risk of hepatitis B recurrence in liver transplant patients. In this article, we highlight the importance of compliance to these therapies and provide further data that with potent, newer HBV antiviral therapies, the shift away from long term hepatitis B immunoglobulin has begun. Please cite this paper as: Ahn J, Cohen SM. Prevention of Hepatitis B Recurrence in Liver Transplant Patients Using Oral Antiviral Therapy without Long-Term Hepatitis B Immunoglobulin. Hepat Mon. 2011; 11(8):638-45. [DOI: 10.5812/kowsar.1735143X.717] © 2011 Kowsar M.P.Co. All rights reserved.

Implications of the changes in the levels of HBV DNA and HBsAg during the treatment of chronic hepatitis B

With the development of new drugs, there has been a significant progression in the treatment of viral hepatitis B over the past five years. Based on their effect mechanisms, the currently available seven different drugs can be classified either as those of the interferon group or those of the nucleoside analogue group. Despite the pharmacological advances, it is still rare to achieve sustained response. The chances of a long-term inactive hepatitis stage, however, have greatly increased with the growing opportunities for personalized pharmacological treatment based on the selection of the correct type of drug, the timely modification of therapy in case of ineffectiveness and the determination of the optimal time and length of the therapy. For this, it is necessary to monitor several predictive, non-invasive biomarkers. For the initiation of the therapy, the most important markers are HBeAg, alanine-aminotranferase and HBV DNA serum levels and the viral genotype. During therapy, quantitative monitoring of the HBV DNA and HbsAg levels helps most to differentiate between those who will respond fast, those who will need longer treatment and those who are unlikely to respond and therefore need alternative drug therapy. A rapid decrease in or disappearance of HBsAg is predictive of successful response during interferon therapy, while changes in the HBV DNA level are more informative during treatment with nucleoside analogues. It is expected that information on the effects of combination therapy will become available soon and this may alter both the currently recommended treatment and monitoring strategy.

Combined antiviral therapy of hepatitis C virus in dialysis patients: meta‐analysis of clinical trials

The efficacy and safety of combined interferon (IFN) plus ribavirin in patients on long-term dialysis and chronic hepatitis C remains unclear, although a number of small clinical trials have addressed this issue. We evaluated the efficacy and safety of combination antiviral therapy (conventional or pegylated interferon plus ribavirin) in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcome was sustained virological response (SVR) (as a measure of efficacy); the secondary outcome was drop-out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. We identified 10 clinical studies (151 unique patients), one (10%) of which was a controlled clinical trial. Most (97.4%) patients were on long-term haemodialysis. The summary estimate for SVR and drop-out rate was 56% [95% Confidence Intervals (95% CI) 28-84] and 25% (95% CI, 10-40), respectively. The most frequent side effects requiring interruption of treatment were anaemia (26%) and heart failure (9%). These results occurred irrespective of type of interferon (conventional or peg-IFN, peg-IFNalfa-2a or alfa-2b), trial design (controlled or cohort study), or clinical characteristics of patients (naïve, nonresponders or relapsers). The studies were heterogeneous with regard to SVR and drop-out rate. Combination antiviral therapy (interferon plus ribavirin) gives encouraging results in terms of efficacy and safety among dialysis patients even if the limited number of patients enrolled in our meta-analysis hampers definitive conclusions.

Necrotic arm lesions in an intravenous drug user

A 62-year-old woman with a history of long-term intravenous drug use and chronic Hepatitis C virus infection was admitted to another hospital unresponsive with profound hypotension. Her symptoms were attributed to a drug overdose leading to a depressed mental status, and possibly septic shock with aspiration pneumonia. She was placed on mechanical ventilation, and treated with vasopressors, high-dose corticosteroids and several broad-spectrum antibiotics. Blood and urine cultures were negative. When she failed to improve after 1 week she was transferred to the intensive care unit at our institution. On transfer, she was unresponsive, intubated, on mechanical ventilation, and hypotensive on vasopressors. We also noted that she had multiple ulcerated skin lesions on both upper extremities (Fig. 1). The lesions involved the dorsum of both hands and wrists, medial aspects of both arms, and the left antecubital fossa. The edges of the lesions were necrotic and the base was macerated. The WBC count was 22,500 mm with 85% neutrophils and 7% band forms. The creatinine was 3 mg/dL. An acute renal failure was attributed to acute tubular necrosis. HIV testing was negative. The CT scans of the chest, abdomen, pelvis, and MRI of the head were unrevealing, and a lumbar puncture was unremarkable. A skin biopsy of the leading edge of the ulcer was performed.

Low hepatitis B immunogenicity of a hexavalent vaccine widely used in Germany: results of the German Health Survey for Children and Adolescents, 2003–2006

The success of childhood vaccination against hepatitis B relies on persistence of immunity into adolescence and adulthood. In 2000, two hexavalent vaccines with a hepatitis B component (Hexavac, Infanrix hexa) were introduced in Germany. Hexavac was withdrawn in 2005 amidst concerns about its long-term hepatitis B protection. We compared hepatitis B surface antibody (anti-HBs) levels in children fully vaccinated with Hexavac or Infanrix hexa (n=477) in a secondary data analysis of a large cross-sectional health survey in Germany. On average 2.4 years after vaccination, 25.3% of Hexavac vaccinees had anti-HBs levels <10 mIU/ml (95% CI 19.0-32.8) compared to 4.7% of Infanrix hexa vaccinees (95% CI 2.4-8.9). These findings suggest that short-term hepatitis B immunogenicity in Hexavac vaccinees may also be weaker. Further studies are warranted to assess whether Hexavac vaccinees should be re-vaccinated or receive a booster vaccination before these birth cohorts reach adolescence.

HBIg Discontinuation with Maintenance Oral Anti-viral Therapy and HBV Vaccination in Liver Transplant Recipients

Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation. To describe results of a protocol at our center including HBV vaccination and HBIg discontinuation. All patients received HBIg therapy and an oral anti-viral agent from the time of transplant. Patients transplanted for HBV with a stable post-operative clinical course underwent HBV vaccination and HBIg discontinuation. After HBIg discontinuation, patients were monitored for HBV recurrence for at least one year. Recurrence was defined as either viral (HBV-DNA 10(4) copies/ml on two consecutive occasions) or hepatitis (viral recurrence with elevated liver transaminases). Of 1182 recipients, 36 (3%) had HBV. Twenty-four were excluded from the protocol, and the remaining 12 patients underwent HBIg withdrawal. Median age at HBIg discontinuation was 56 (range, 36-70) years, median time from transplant to HBIg discontinuation was 62.8 (range, 27.5-128) months, and median time of follow-up after discontinuation was 27.4 (range, 13-69) months. Of the 12 patients vaccinated, no patients maintained HBSAb >or= 10 IU/l at last follow-up. There was no viral or hepatitis recurrence and no deaths or graft loss. HBIg discontinuation with maintenance oral anti-viral monotherapy is safe and effective for HBV liver transplant recipients. Vaccination is not effective in this population.

Recipient age affects long-term outcome and hepatitis C recurrence in old donor livers following transplantation

We studied the role of donor and recipient age in transplantation/ischemia-reperfusion injury (TIRI) and short- and long-term graft and patient survival. Eight hundred twenty-two patients underwent deceased donor liver transplantation, with 197 donors being > or = 60 years old. We evaluated markers of reperfusion injury, graft function, and clinical outcomes as well as short- and long-term graft and patient survival. Increased donor age was associated with more severe TIRI and decreased 3- and 5-year graft survival (73% versus 85% and 72% versus 81%, P < 0.001) and patient survival (77% versus 88% and 77% versus 82%, P < 0.003). Hepatitis C virus (HCV) infection and recipient age were the only independent risk factors for graft and patient survival in patients receiving an older graft. In the HCV(+) cohort (297 patients), patients > or = 50 years old who were transplanted with an older graft versus a younger graft had significantly decreased 3- and 5-year graft survival (68% versus 83% and 64% versus 83%, P < 0.009). In contrast, HCV(+) patients < 50 years old had similar 3- and 5-year graft survival if transplanted with either a young graft or an old graft (81% versus 82% and 81% versus 82%, P = 0.9). In conclusion, recipient age and HCV status affect the graft and patient survival of older livers. Combining older grafts with older recipients should be avoided, particularly in HCV(+) patients, whereas the effects of donor age can be minimized in younger recipients.

Liver transplantation in viral hepatitis: Prevention of recurrence

End-stage liver disease caused by the hepatitis B and C viruses (HBV and HCV) are major indications for liver transplantation. Outcome depends largely on the prevention of allograft reinfection. The advent of long-term hepatitis B immune globulin administration and the introduction of new antiviral agents were a major breakthrough in the management of these patients. Today, survival after orthotopic liver transplantation (OLT) is similar to that of patients transplanted for HBsAg-negative liver disease, and the risk of recurrence is below 10%. In contrast, HCV reinfection is almost constant and significantly impairs patient and graft survival. Factors that may influence disease severity and consequently progression of HCV graft injury remain unclear. Pre-transplantation and prophylactic post-transplantation antiviral treatments are limited by low applicability and poor tolerance. Treatment of established graft lesions with combination therapy gave promising results, with sustained virological response in 25-45% of patients, but indications, modality and duration of treatment should be assessed.

Do we really need long-term hepatitis B hyperimmune globulin? What are the alternatives?

1. The outcomes of liver transplantation for patients with hepatitis are the best for any diagnosis. 2. Prevention of HBV re-infection is the key to excellent outcomes after liver transplantation. 3. The use of hepatitis B immunoglobulin to prevent HBV re-infection is effective, but costly and with side effects. 4. Effective prophylaxis against HBV re-infection can now be accomplished with combination nucleoside/nucleotide anti-virals.

Long-term hepatitis C internal ribosome entry site-dependent gene expression mediated by phage φC31 integrase in mouse model

Background The lack of a robust small animal model for hepatitis C virus (HCV) has hindered the development of novel drugs, including internal ribosome entry site (IRES) inhibitors. Phage φC31 integrase has emerged as a potent tool for achieving long-term gene expression in vivo. This study utilized φC31 integrase to develop a stable, reproducible and easily accessible HCV IRES mouse model. Methods φC31 integrase plasmid and the reporter vector, HCV-IRES–luciferase expression cassette (containing an attB site), was codelivered to murine livers using high pressure tail vein injection. HCV IRES-dependent translation refected by luciferase expression was accurately monitored in vivo by bioluminescence imaging. Genomic integration of the transgene was confirmed by partial hepatectomy and nested PCR. An HCV IRES-targeted short hairpin RNA (shRNA) expression plasmid, sh184, was hydrodynamically transfected into mouse liver to study its inhibition efficacy in vivo. Results φC31 integrase mediated intramolecular recombination between wild-type attB and attP sites in mice. The expression of luciferase was stable after 30 days post-transfection and remained so for 300 days only in the livers of mice that were coinjected with the integrase-encoding plasmid. Luciferase levels reduced dramatically after hydrodynamic transfection of sh184. Conclusions These results indicate that this mouse model provides a powerful tool for accurate and long-term evaluation of potential anti-IRES compounds in vivo.