Search

Background & Aims Autoimmune hepatitis (AIH) is an immune-mediated disease with no curative treatment. Regulatory T cell (Treg) therapy is potentially curative in AIH given the critical role of Tregs in preventing autoimmunity. To work effectively, adoptively transferred Tregs must migrate to and survive within the inflamed liver. We conducted a proof-of-concept study aiming to assess the safety and liver-homing properties of good manufacturing practice (GMP)-grade autologous Tregs in patients with AIH. Methods Autologous polyclonal GMP-grade Tregs were isolated using leukapheresis and CliniMACS, labelled with indium tropolonate and re-infused intravenously to 4 patients with AIH. GMP-Treg homing to the liver was investigated with longitudinal gamma camera and SPECT-CT scanning. GMP-Treg immunophenotype, function and immunometabolic state were assessed during the study. Results We observed that the isolated Tregs were suppressive and expressed CXCR3, a chemokine receptor involved in recruitment into the inflamed liver, as well as Treg functional markers CD39, CTLA-4 and the transcription factor Foxp3. Serial gamma camera and SPECT-CT imaging demonstrated that 22–44% of infused Tregs homed to and were retained in the livers of patients with autoimmune hepatitis for up to 72 h. The infused cells did not localise to any off-target organs other than the spleen and bone marrow. GMP-Tregs were metabolically competent and there were no infusion reactions or high-grade adverse effects after Treg infusion. Conclusion Our novel findings suggest that the liver is a good target organ for Treg cellular therapy, supporting the development of clinical trials to test efficacy in autoimmune hepatitis and other autoimmune liver diseases. Lay summary Autoimmune liver diseases occur when the body’s immune cells target their own liver cells. Regulatory T cells (Tregs) prevent autoimmunity, thus they are a potential therapy for autoimmune liver diseases. In patients with autoimmune hepatitis, Treg infusion is safe, with nearly a quarter of infused Tregs homing to the liver and suppressing tissue-damaging effector T cells. Thus, Tregs are a potentially curative immune cell therapy for early autoimmune liver diseases., Graphical abstract Unlabelled Image, Highlights • Tregs from patients with autoimmune hepatitis are suppressive, possess functional markers CD39 and CTLA-4, and express CXCR3. • Treg infusion in autoimmune liver disease is safe without any side effects. • 22-44% of infused Tregs home to and were retained in the livers of patients with autoimmune hepatitis for up to 72 hours. • GMP-Tregs from patients with autoimmune hepatitis were metabolically competent.

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.

Objective: The aim of this report is to describe a new ultrasound guided technique for carpal tunnel injection and median nerve hydrodissection using distal to proximal approach. Methods: From 2015 to 2019, 827 consecutive injections by distal-to-proximal approach were included using coding information to check for post-procedural skin hypopigmentation, hematoma, seroma, nerve injury, or vascular injury. Results: There were no occurrences of post-procedural skin-hypopigmentation, hematoma or seroma formation, or neurovascular injury. Conclusions: The distal approach carpal tunnel injection is a safe and effective method. It may directly inject the medication into carpal tunnel to avoid skin hypopigmentation from steroid side effect with previous report method, also it may release adhesion of median nerve with surrounding soft tissue by hydrodissection. It helps median nerve compression at outlet of carpal tunnel.

SORT1 is strongly associated with plasma lipid traits and coronary artery disease. The protein it encodes, sortilin is a multi-ligand receptor involved in trafficking of proteins from the Golgi to the lysosome. Hepatic sortilin overexpression reduces VLDL secretion, but the effects of loss of sortilin function on apolipoprotein B100 (apoB) and VLDL secretion have been contradictory and perplexing. Conflicting studies have variously reported increased and decreased apoB/VLDL secretion in response to loss of sortilin, but used a variety of different models and methods of ablating sortilin function. To resolve this, we first measured VLDL secretion in Sort1 knockout (KO) mice on a chow diet and observed no differences in either apoB or TG secretion. ApoB secretion was similarly unaffected in Sort1 KO primary hepatocytes or in McA-RH7777 cells treated with siRNA to knockdown sortilin. We concluded that in a basal secretory state, loss of sortilin alone does not impact apoB secretion, leading us to test if differences in secretory state might explain the discrepancies in published results. We found that when hAPOB was overexpressed, Sort1 knockdown further increased its secretion. The reports of increased VLDL secretion with Sort1 knockout occurred with apoB overexpression, or on high fat diet (HFD); consistent with our hypothesis that secretory overload or metabolic stress are required to uncover the deficiency phenotype. We placed Sort1 KO mice on a 45% HFD for 12 weeks and observed a significant increase in VLDL secretion compared to controls. In addition, when we lipid-loaded hepatocytes with oleic acid or palmitic acid, apoB secretion was increased, and Sort1 knockdown further increased this compared to control. We treated cells with Tunicamycin to induce ER stress, and found that apoB secretion was decreased in the control group was observed, but not in the absence of Sort1, suggesting that sortilin regulates apoB secretion the cell is stressed. Based on these data, we propose that hepatic sortilin regulates the post-ER fate of apoB for either degradation or export; thereby coordinating intracellular apoB metabolism in response to the number and quality of apoB particles that reach the Golgi, and the level of post-ER pre-secretory proteolysis activity.

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1-infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.

The immune system evolved to launch effective and specific responses against pathogens. A key feature of this defense mechanism is its ability to differentiate between self and nonself. However, in autoimmune diseases, the host’s immune system fails to discriminate self versus foreign. The CNS is further protected by the blood–brain barrier. In spite of its ‘immune privilege,’ the brain is not protected from autoimmunity; perhaps paradoxically xenoantibodies can be used to treat neurological diseases. We describe patents covering treatment methods for CNS diseases with suspected or demonstrated autoimmune etiology. These include multiple sclerosis and, Alzheimer’s and Parkinson’s disease. The goal is to less invasively, yet efficiently, treat neurological diseases. Although autoimmune responses are often detrimental, recent studies have begun to harness, boost and induce immune responses as a mechanism of treatment. The patents discussed herein highlight new treatments for Alzheimer’s and Parkinson’s disease, multiple sclerosis, and seizure disorders.

Research into the diagnosis and treatment of central nervous system (CNS) diseases has been enhanced by rapid advances in nanotechnology and an expansion in the library of nanostructured carriers. This review discusses the latest applications of nanomaterials in the CNS with an emphasis on brain tumors. Novel administration routes and transport mechanisms for nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents to bypass or cross the blood brain barrier (BBB) are also discussed. These include temporary disruption of the BBB, use of impregnated polymers (polymer wafers), convection-enhanced delivery (CED), and intranasal delivery. Moreover, an in vitro BBB model capable of mimicking geometrical, cellular and rheological features of the human cerebrovasculature has been developed. This is a useful tool that can be used for screening CNS nanoparticles or therapeutics prior to in vivo and clinical investigation. A discussion of this novel model is included.

Summary Background Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. Methods This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. Findings Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0–17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1–1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). Interpretation Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. Funding Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

The thermal volatilization analysis (TVA) and subambient thermal volatilization analysis (SATVA) techniques are described. In addition to rate profiling of the volatile product flux of thermal degradation under high-vacuum conditions through measurement of pressure in the vacuum line as a function of sample temperature, the TVA technique is shown to afford a convenient method for an isolation, on the basis of volatility under high-vacuum conditions, of product fractions of thermal degradation for subsequent spectroscopic analysis. The capacity and flexibility of TVA as a platform for these analyses are illustrated in a case study format by degrading poly(bisphenol A, 2-hydroxy propylether). The overall degradation process is quantified, and most significant pathways of thermolysis are identified through subsequent spectroscopic analysis of products of decomposition. The design and construction of a modified vacuum-tight long-path gas IR cell, as an interface allowing for the application of Fourier transform infrared spectroscopy (FT-IR) for the on-line analysis of volatile products of polymer degradation, is detailed. Proof of concept and application of this new analytical technique, subsequently referred to as TVA/FT-IR, is illustrated through the examination of appropriate aspects of the thermal degradation of polymethyl methacrylate polymers.

Patient and public involvement (PPI) has become increasingly important to ensure the needs of patients are fully considered when they participate in clinical trials. Most funders now require a plan for PPI in grant applications. When fully embraced and correctly implemented, PPI adds an important dimension to clinical trials, and its continuing development is critical if we are to maintain the public's support for clinical research. The development of a PPI panel for the National Institute for Health Research Birmingham Liver Biomedical Research Unit (NIHR BRU) has helped to: promote research locally and nationally; improve recruitment to and participation in trials; promote public engagement and education activities; and improve the quality and relevance of consent forms and information sheets for participants. The NIHR BRU has the support of a PPI panel which constantly champions the research being undertaken to the wider community. This paper describes how the panel was established and why it is so effective.

Introduction There are still no licensed therapies for non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed in type 2 diabetes, and are promising therapeutic candidates for NASH, yet no trial data exists on their efficacy in this setting. The histological efficacy and safety of the long-acting GLP-1 analogue, liraglutide, was assessed in patients with NASH. Method In the Liraglutide Efficacy and Action in NASH (LEAN) trial (ClinicalTrials.gov NCT01237119) overweight patients with biopsy-confirmed NASH were randomised (1:1) to receive 48-weeks treatment with once-daily, subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Randomisation was stratified by trial centre (n = 4) and diabetes status. The primary outcome measure as assessed centrally by two independent histopathologists (RMB, SGH) was improvement in liver histology, defined as ‘resolution of definite NASH’ and no worsening in fibrosis from baseline to end-of-treatment (EOT). Preliminary analyses were performed by intention-to-treat. Results Of the 52 patients randomised (mean age 51 years, 60% male, 33% type 2 diabetes, 52% F3/F4 Kleiner fibrosis stage), 45 patients underwent EOT liver biopsies. The primary end-point was met, and 9 (39%) of 23 patients on liraglutide had resolution of definite NASH compared to 2 (9%) of 22 patients on placebo (p = 0.019). Only 2 (9%) patients on liraglutide had worsening of fibrosis compared to 8 (36%) on placebo (p = 0.026). Moreover, liraglutide reduced weight (–5.3 vs. –0.6 kg, p = 0.001), BMI (–1.8 vs. –0.3 kg/m 2 , p = 0.003), and fasting glucose (–1.0 vs –0.7 mmol, p = 0.005) compared to placebo. Reductions in ALT (–27 vs. –10, p = 0.126) and HbA1c (–0.5% vs. –0.03, p = 0.07) were also seen with liraglutide, albeit not significant versus placebo. There were no treatment differences in lipid profile or systolic BP. There were no serious adverse events in patients on liraglutide, which was well-tolerated with only 2 (8%) of 26 patients withdrawing from treatment due to drug-related gastro-intestinal (nausea, diarrhoea) side effects. Conclusion In a randomised controlled trial liraglutide met the primary end-point of histological clearance of NASH, and a reduction in progression of fibrosis. It was also safe and well-tolerated. Phase III registration trials are now warranted for GLP-1 therapy in patients with NASH. Disclosure of interest M. Armstrong Grant/ Research Support from: Novo Nordisk – free drug for the trial, P. Gaunt: None Declared, G. Aithal: None Declared, R. Parker: None Declared, D. Barton: None Declared, D. Hall: None Declared, K. Guo: None Declared, G. Abouda: None Declared, M. Aldersley: None Declared, S. Gough Grant/ Research Support from: Novo Nordisk, Speaker Bureau of: Novo Nordisk, J. Tomlinson: None Declared, R. Brown: None Declared, S. Hubscher: None Declared, P. Newsome Grant/ Research Support from: Novo Nordisk – free drug for the trial, Speaker Bureau of: Novo Nordisk.

Background Adipose tissue insulin resistance and lipotoxicity are key pathognomonic features in non-alcoholic steatohepatitis (NASH). Liraglutide is a once daily, glucagon-like peptide 1 (GLP-1) analogue that significantly improves glycaemic control, weight, and hepatic steatosis. The aim of this phase 2 study was to determine the effect of liraglutide on insulin sensitivity (hepatic, muscle, adipose), hepatic lipogenesis, and markers of adipose inflammation. Methods 14 patients with biopsy-proven NASH were randomly assigned to either 1·8 mg liraglutide or placebo (once a day subcutaneously) for 12 weeks as part of the metabolic substudy of the double-blind, randomised placebo-controlled LEAN trial. At baseline and 12 weeks, patients underwent paired two-step hyperinsulinaemic euglycaemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. Serum adipocytokines were measured with Fluorokine MAP multiplex kits (R&D Systems, UK). In-vitro isotope experiments were performed with Huh-7 and primary human hepatocytes. The LEAN trial is registered with ClinicalTrials.gov, number NCT01237119. Findings Liraglutide significantly decreased weight, waist circumference, HbA 1c , fasting glucose, LDL, and liver enzymes compared with placebo. Liraglutide significantly increased the suppression of hepatic glucose production with low-dose insulin. Liraglutide significantly decreased circulating non-esterified fatty acid (NEFA) in the fasting, low-dose, and high-dose insulin states. Liraglutide significantly reduced the insulin concentration required to half-maximally suppress circulating NEFA and significantly decreased adipose tissue lipolysis, as shown by a reduction in interstitial fluid glycerol concentrations. Furthermore, liraglutide significantly improved serum markers of adipose inflammation—namely, leptin, adiponectin, and chemokine ligand 2. In addition, liraglutide significantly decreased de-novo lipogenesis in vivo, as measured by incorporation of deuterated 2H 2 0 into palmitate, compared with placebo. In support of our clinical observations, in-vitro experiments using both the Huh-7 cell line and primary cultures of human hepatocytes showed decreased de-novo lipogenesis, measured by incorporation of 14C-acetate into cellular lipid after treatment with GLP-1 (exendin-4). Interpretation Liraglutide significantly reduces metabolic dysfunction, hepatic lipogenesis, hepatic and adipose insulin resistance, and adipose inflammation in patients with NASH. GLP-1 analogue therapy might be a novel treatment for patients with this condition. Funding Wellcome Trust, National Institute of Health Research, Novo Nordisk.

Background Prevention of recurrent hepatitis C virus (HCV) infection after liver transplantation is a major unmet clinical need. ITX5061 is a small molecule antagonist of scavenger receptor B-I that prevents HCV entry and infection in vitro. The aim of this phase 1 study was to determine safety and efficacy of ITX5061 to prevent HCV allograft infection. Methods In this phase 1b single-centre, prospective, open-label study, we included 23 consecutive patients with HCV infection (21 male) undergoing liver transplantation. The first 13 patients did not receive study drug (controls). The subsequent ten patients received ITX5061 150 mg orally immediately before liver transplantation, after transplantation, and daily for 1 week. Plasma HCV RNA was measured at 13 predefined time-points during the first week and weekly thereafter for the first month, allowing detailed viral kinetic monitoring. Plasma samples were collected to determine ITX5061 before and after transplantation and measured with liquid chromatography and mass spectrometry. This trial is registered with ClinicalTrials.gov, number NCT01292824. Findings 13 recipients were infected with HCV genotype 1. There was no significant difference between untreated and treated patients at baseline and all patients survived 1 month after liver transplantation. ITX5061 treatment was well tolerated with no difference in the nature or frequency of adverse events between the treated and untreated patients. Oral absorption of ITX5061 was demonstrated, with measurable plasma concentrations before transplatation and daily for 1 week after transplantation. HCV RNA concentrations decreased during the first 24 h but remained detectable for all patients at all times during treatment and follow-up. Compared with values measured during the anhepatic phase of surgery, the median reduction in HCV RNA was greater for treated patients at all timepoints (∼ 1 log 10 difference during 7 days' treatment). The maximum decline in HCV RNA was greater than 2 log 10 in eight of ten treated patients compared with six of 13 untreated patients. In patients with genotype 1 disease (n=6), treatment was associated with a sustained reduction in HCV RNA titre (all >2 log 10 ) during 7 days compared with the control group (n=7), none of whom achieved a 2 log 10 reduction at any time. After withdrawal of treatment, HCV RNA increased in all patients. Interpretation Our findings show that treatment with ITX5061, an inhibitor of HCV entry, is safe and well tolerated in liver transplantation. ITX5061 affects plasma HCV RNA kinetics, and a substantial reduction in plasma HCV RNA during treatment was recorded. These findings support further investigation into the efficacy of ITX5061 in HCV- infected patients undergoing liver transplantation. Funding iTherX, Inc., NIHR Birmingham Liver Biomedical Research Unit.

Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A9Hern9s single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. Trial registration clinicaltrials.gov NCT01237119.

Background After liver transplantation in patients infected with hepatitis C virus (HCV), reinfection of the transplanted liver is universal. The targeting of viral entry at the time of transplantation is therefore an attractive strategy. An understanding of the mechanisms and kinetics of this process will allow rational studies of small molecule inhibitors or neutralising antibodies that target HCV entry. Methods As part of a proof of concept study of ITX5061 (a small molecule antagonist of the HCV entry receptor, scavenger receptor B-I), we have studied detailed HCV kinetics. HCV RNA was quantified in plasma before and after liver transplantation. This study is registered with ClinicalTrials.gov, number NCT01292824. Findings 13 patients were studied (median age 57 years, 11 male). Seven patients were infected with genotype 1, four with genotype 3, and one each with genotypes 2 and 4. During the period when no blood flowed through the liver there was a slow decline in plasma HCV RNA. After implantation of the donor liver there was a rapid decrease in HCV RNA in the plasma indicating entry of viral particles into the liver. Typically, there was a 90–99% decrease in HCV RNA at 4 h after implantation. This decrease continued until 12 h after implantation in all patients, and the initial rapidity of HCV RNA decline suggests the presence of specialised clearance systems in the liver. After this decrease, five patients showed a steady increase in plasma HCV RNA, which returned to baseline within 96 h indicating a rapid establishment of productive infection in the allograft. In the remaining eight patients there was a prolonged nadir for up to 21 days after transplant suggesting innate immune control in the transplanted liver. No differences in kinetics were observed between patients infected with different viral genotypes, or in the degree of liver injury at the time of transplantation. Interpretation These marked differences in viral kinetics have major implications for trial design and probably have important biological significance in innate control of infection. Funding National Institute for Health Research.