Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

Hepatitis C Virus Recurrence Occurs Earlier in Patients Receiving Donation After Circulatory Death Liver Transplant Grafts Compared With Those Receiving Donation After Brainstem Death Grafts.

INTRODUCTION: Hepatitis C virus (HCV)-related cirrhosis remains the commonest indication for liver transplantation worldwide, yet few studies have investigated the impact of donation after circulatory death (DCD) graft use on HCV recurrence and patient outcomes. DCD grafts have augmented the limited donor organ pool and reduced wait-list mortality, although concerns regarding graft longevity and patient outcome persist. METHODS: This was a single-center study of all HCV + adults who underwent DCD liver transplantation between 2004 and 2014. 44 HCV+ patients received DCD grafts, and were matched with 44 HCV+ recipients of donation after brainstem death (DBD) grafts, and their outcomes examined. RESULTS: The groups were matched for age, sex, and presence of hepatocellular carcinoma; no significant differences were found between the group's donor or recipient characteristics. Paired and unpaired analysis demonstrated that HCV recurrence was more rapid in recipients of DCD organs compared with DBD grafts (408 vs 657 days; P = .006). There were no significant differences in graft survival, patient survival, or rates of biliary complications between the cohorts despite DCD donors being 10 years older on average than those used in other published experience. CONCLUSIONS: In an era of highly effective direct acting antiviral therapy, rapid HCV recrudescence in grafts from DCD donors should not compromise long-term morbidity or mortality. In the context of rising wait-list mortality, it is prudent to use all available sources to expand the pool of donor organs, and our data support the practice of using extended-criteria DCD grafts based on donor age. Notwithstanding that, clinicians should be aware that HCV recrudescence is more rapid in DCD recipients, and early post-transplant anti-viral therapy is indicated to prevent graft injury.

New treatments for hepatitis C virus (HCV): scope for preventing liver disease and HCV transmission in England.

New direct-acting antivirals have the potential to transform the hepatitis C (HCV) treatment landscape, with rates of sustained viral response in excess of 90%. As these new agents are expensive, an important question is whether to focus on minimizing the consequences of severe liver disease, or reducing transmission via 'treatment as prevention'. A back-calculation model was used to estimate the impact of treatment of mild, moderate and compensated cirrhosis on incident cases of HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC). In addition, a dynamic model was used to determine the impact on incidence and prevalence of chronic infection in people who inject drugs (PWID), the main risk group in England. Treating 3500 cirrhotics per year was predicted to reduce ESLD/HCC incidence from 1100 (95% CrI 970-1240) cases per year in 2015 to 630 (95% CrI 530-770) in 2020, around half that currently expected, although treating moderate-stage disease will also be needed to sustain this reduction. Treating mild-stage PWID was required to make a substantial impact on transmission: with 2500 treated per year, chronic prevalence/annual incidence in PWID was reduced from 34%/4.8% in 2015 to 11%/1.4% in 2030. There was little overlap between the two goals: treating mild stage had virtually no impact on ESLD/HCC within 15 years, but the long timescale of liver disease means relatively few PWID reach cirrhosis before cessation of injecting. Strategies focussing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

Outcome of liver transplantation in patients with hereditary bleeding disorders: a single centre UK experience.

INTRODUCTION: Patients with hereditary bleeding disorders who have developed end-stage liver disease as a consequence of hepatitis C infection (HCV) acquired from factor concentrates prior to the introduction of viral inactivation continue to be referred for liver transplantation. METHODS: A retrospective review of case notes and electronic records was performed on all patients with bleeding disorders who have undergone liver transplantation at the University Hospital Birmingham (UHB). RESULTS: Between 1990 and 2014, 35 liver transplants have been performed in 33 patients with hereditary bleeding disorders. The indication for transplantation was mainly end-stage liver disease secondary to HCV. Five patients had human immunodeficiency virus (HIV) co-infection. No excess mortality due to bleeding occurred in the peri or postoperative period. Median overall survival post transplant is 9.7 years. Overall survival rates at 1, 3 and 5 years are 90%, 72% and 64% respectively. The predominant cause of mortality was liver failure secondary to either recurrent HCV or recurrent hepatocellular carcinoma (HCC). The median overall survival in patients with HIV co-infection is shorter than in those with mono-infection but this is not statistically significant. Patients with a pre-existing HCC had a statistically significant shorter survival (2.4 years vs. 13.6 years, P = 0.007). CONCLUSION: Liver transplantation has become an accepted treatment option for patients with hereditary bleeding disorders and HCV associated end-stage liver disease with survival rates similar to non-bleeding disorder patients.

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Evolution and emergence of a new era of antiviral treatment for chronic hepatitis C infection.

Chronic hepatitis C virus (HCV) infection is a major public health burden associated with significant morbidity and mortality. The approval of telaprevir and boceprevir for use with interferon and ribavirin in chronic HCV infection significantly increased viral eradication but has been accompanied by increased adverse events and therefore inferior clinical tolerance. Newer classes of antiviral agents, such as directly acting antiviral and host-targeting agents, offer a combination of drugs without the need for interferon and can achieve better response rates with a shorter duration of treatment. This offers an exciting prospect in the new era of antiviral treatment for HCV infection.

Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice.

BACKGROUND: Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. OBJECTIVES: To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. METHODS: We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. RESULTS: Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator's first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). CONCLUSIONS: Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.

Despite poor interferon response in advanced hepatitis C virus infection, models of protease inhibitor treatment predict maximum treatment benefit.

BACKGROUND: Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy. AIM: To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin. METHODS: Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches. RESULTS: Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period. CONCLUSIONS: Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients.

BACKGROUND: The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs. AIMS: To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection. METHODS: These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers. RESULTS: We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients. CONCLUSIONS: These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

UKHCDO guidelines on the management of HCV in patients with hereditary bleeding disorders 2011.

Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group.

Ante-natal screening and post-natal follow-up of hepatitis B in the West Midlands of England.

BACKGROUND: We established at Queen Elizabeth Hospital in Birmingham a post-natal follow-up care service for hepatitis B virus (HBV) positive women diagnosed through ante-natal screening. AIM: Virological and clinical follow-up of HBsAg positive mothers detected through ante-natal screening in Birmingham. DESIGN: Retrospective observational study. METHOD: We evaluated 117 post-natal mothers with chronic HBV infection between April 2003 and December 2006. Patients were first seen at least 3 months post-delivery and followed up. RESULTS: Most of the women were of Asian or African origin (107 of 117 patients). Five out of 117 (4%) patients had undergone serum HBsAg clearance by the time of post-natal review, and 112 patients had persisting HBsAg-positivity (seven HBeAg positive and 105 HBeAg negative). HBeAg positive women were younger than HBeAg negative patients (median 21 vs 30-years old). Fifty percent of HBeAg negative women had detectable serum HBV DNA at the time of initial review. HBeAg positive women had higher serum HBV DNA titres than those negative for HBeAg (median 40 million copies/ml vs 4323 copies/ml). The majority of patients had normal serum transaminases. A single case of clinically significant liver disease was identified in a woman with HBV and delta virus infection. CONCLUSION: Very few women who were diagnosed with chronic HBV infection at ante-natal screening have clinical evidence of liver disease. However, many have high levels of virus replication and remain at risk for the future development of liver disease.

Inferior response of Asian vs non-Asian hepatitis C genotype 3 infection to combination antiviral therapy.

Racial differences in response to treatment of hepatitis C virus (HCV) have been noted in several trials. In this study, we compared the response rate to treatment of Asian patients infected by genotype 3 HCV with non-Asians treated for the same genotype. Sixteen of 38 (42.1%) Asians achieved a sustained virological response (SVR), compared with 41 of 66 (62.1%) Caucasians (P = 0.063). At baseline prior to treatment, Asians had a higher histological fibrosis stage (P = 0.0014), indicating more advanced disease at presentation. In univariable analysis of baseline factors predicting failure to achieve an SVR, Asian ethnicity, fibrosis stage, higher serum aspartate transaminase, bilirubin and alkaline phosphatase, as well as lower white cell count, haemoglobin and platelet count were statistically significant. None of these factors achieved significance in multivariate analysis, possibly because of the relatively small number of patients studied. We have observed an inferior response to treatment of Asian vs Caucasian patients. The poor response probably reflects the more advanced liver disease at baseline observed for Asian British patients.

Incidence and characterization of serum transaminases elevations in pegylated interferon and ribavirin treated patients with chronic hepatitis C.

BACKGROUND: A virological response to pegylated-interferon and ribavirin is typically associated with a prompt fall in serum transaminases. For some patients, transaminases rise during treatment. AIM: To assess the frequency and define factors associated with elevations of serum transaminases. METHODS: A total of 169 treated patients were studied. Transaminase elevations were graded by WHO criteria - grade 0: no value > baseline, grade 1: 1-2x baseline, grade 2: 2.1-5x baseline, grade 3: >5x, grade 4: any rise with evidence of liver failure. Results 60/169 (35%) patients experienced transaminase elevations: 52 grade 1, 6 grade 2, 1 grade 3, 1 grade 4. Overall, end of treatment response and sustained virological response rates were 72% and 55%. Lower rates were observed in the grade 1 elevation group (63% and 40%) compared with patients with grade 0 (79% and 65%) and grade > or =2 elevations (85% and 71%). Grade 1 elevations tended to occur earlier during treatment than grade > or =2 elevations. Transaminase elevations were associated with greater pre-treatment body weight (P = 0.006), steatosis (P = 0.008) and poorer sustained virological response rates (P = 0.007). CONCLUSIONS: Transaminase elevations during treatment of chronic Hepatitis C virus with pegylated interferon and ribavirin are common but rarely severe. Mild rises may reflect ongoing viral activity in treatment non-responders. More significant rises are frequently observed despite a virological response, and may be because of an immuno-modulating effect of interferon in susceptible patients.

Primary hepatocellular cancer in the explanted liver: outcome of transplantation and risk factors for HCC recurrence.

AIM: To evaluate the risk of recurrence of hepatocellular cancer (HCC) after liver transplantation (LT). METHODS: The clinical records of 104 patients with HCC in the explanted liver were examined. RESULTS: HCC recurrence occurred in 12 patients. Recurrence was observed in all patients with a single nodule greater than 5 cm. Among the 5 patients with more than 3 tumours with a maximum diameter of 4.5 cm, no recurrence occurred. The survival rates were 81% and 64% at 1 and 5 years, respectively; the recurrence-free survival at 1 and 5 years was, respectively, 93% and 82%. Pre-LT alpha-fetoprotein (AFP) increased at a greater magnitude in patients who experienced recurrence, compared to those who did not. Tumour diameter, differentiation, satellitosis, AFP and the magnitude of AFP increase were predictive of recurrence. The 1- and 5-year recurrence-free survival for the 68 patients who had a single nodule up to 5 cm, or up to 3 nodules all less than 4.5 cm and with a maximum cumulative diameter of 8 cm, or more than 3 nodules all less than 2.5 cm, were 95% and 92%, respectively. For the 13 patients not meeting these criteria, the 1- and 5-year recurrence-free survival was, respectively, 75% and 54% (log Rank test p=0.019). CONCLUSIONS: Patients with more than 3 small HCC nodules before LT could still have a good outcome without recurrence. A rapid increase in AFP could be useful in identifying patients with a greater risk of post-LT HCC recurrence.