Clearance of Hepatitis C Virus following Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma: Case Report.

Introduction: Patients with advanced hepatocellular carcinoma (HCC) have limited treatment options in the context of decompensated cirrhosis. HCC occurs in patients with hepatitis C virus (HCV) infection and cirrhosis at 1-4% per year. Direct-acting antiviral (DAA) efficacy is decreased in the presence of HCC. We present a case where immunotherapy may have resulted in HCV clearance, when DAA therapy had been ineffective. We hypothesise that immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway can reverse T-cell exhaustion and aid in the clearance of chronic HCV. Case Presentation: This case study describes a male in his 40 s identified by a re-engagement initiative for HCV, who had been unaware of his diagnosis. On further investigation he was found to have compensated for liver cirrhosis and HCC. He was treated with HCV DAA therapy (sofosbuvir/velpatasvir) and then systemic immunotherapy for HCC with atezolizumab and bevacizumab, in an attempt to downstage the disease. Hepatitis C therapy did not achieve sustained virological response, with viral relapse after the end of treatment. This, combined with ongoing alcohol use, resulted in hepatic decompensation and cessation of immunotherapy after the fifth cycle. The HCV RNA subsequently became undetectable without further DAA re-treatment. Conclusion: To our knowledge, this is the first case of HCV clearance after DAA relapse and the timing of this event after immunotherapy suggests a causal link. We hypothesise that this may be due to the reversal of antiviral T-cell exhaustion. This would therefore support further investigation into other chronic viral infections that create tumour associated with immunosuppressive microenvironments.

Falling treatment uptake in the hepatitis C care cascade is a growing threat to achieving elimination.

Most high-income countries are not on track to achieve the World Health Organization hepatitis C elimination targets. As elimination programmes assess growing proportions of patients in community-based pathways, rates of treatment uptake may fall. We aimed to identify factors associated with DAA treatment uptake and measure changes in their prevalence over time. We performed a time-to-treatment analysis on 2728 patients approved for hepatitis C Direct-Acting Antiviral treatment in the North Central London region between January 2016 and October 2019. We investigated the association between treatment uptake and factors including assessment/treatment setting (hospital, drug service or prison), patient age, gender, injection drug use, harmful alcohol use, cirrhosis status and previous treatment. The likelihood of treatment uptake was reduced by three independent risk factors. These included assessment setting: prison-based or drug-service pathways (aHR 0.29 or 0.81 vs. hospital outpatient pathway, 95% CI 0.21-0.40 and 0.70-0.94 respectively, p < .001); being UK-born (aHR 0.89 vs. non-UK born, 0.82-0.98, p = .01); and history of harmful alcohol use (aHR 0.84 vs. no history, 0.72-0.99, p = .04). The average number of these risk factors for not starting treatment per patient increased over time (R2  = 0.66 p < .001). Independent of these, there was an additional 5% reduction in rate of treatment initiation in each successive year of the programme (aHR 0.95, 0.91-0.99, p = .02). In conclusion, disengagement from care before treatment uptake was found to be a growing threat to elimination. Despite provision of community-based test-to-cure pathways, there are persistent barriers to treatment uptake and these are increasing over time.

Hepatic encephalopathy: a rare cause of focal seizures in chronic liver disease.

Hepatic encephalopathy (HE) is an extremely rare cause of focal seizures and is usually a diagnosis of exclusion when more commoner causes such as infection, autoimmune and malignancy have been discounted. The literature reports patients with generalised cerebral oedema and rarely status epilepticus, but these are often in the context of acute liver failure as opposed to chronic liver disease. Here we discuss a case of HE leading to focal neurological deficits and seizures in a 48-year-old woman with a background of chronic alcoholic liver disease. MRI scan showed extensive left-sided tempo-parietal-occipital cortical oedema and electroencephalogram showed widespread moderate HE with runs of epileptiform discharges. The treatment involves antiepileptic therapy as well as standard management of HE with laxatives, rifaximin and optimisation of nutrition.

Downstaging for hepatocellular cancer: harm or benefit?

Downstaging of hepatocellular carcinoma (HCC) to enable liver transplantation has become an area of intense interest and research. It may allow a curative option in patients outside widely accepted transplantation criteria, with outcomes that, in some studies, are comparable to transplantation for patients within criteria. There have been conflicting opinions on the best downstaging protocols, criteria for downstaging eligibility and for assessment of response. We therefore aimed to review the literature and evidence for downstaging, as well as considering its drawbacks. CONCLUSION: Pooled analyses have suggested success in down staging in about half of patients treated, but with higher recurrence rates than patients initially within transplantation criteria. Studies with strict inclusion criteria and mandatory waiting time before transplantation reported survival equivalent to patients who did not require downstaging. In carefully selected patients, there is a role for down staging to provide the chance of transplantation and cure, with acceptable outcomes. Further multi center, well-designed studies are required to clarify who will mostly benefit. Until such data is available, downstaging criteria should be stated within transplantation programs and relevant decisions should be discussed by multidisciplinary teams.

Safe sedation practices among gastroenterology registrars: do we need more training?

Endoscopy training is a central component of gastroenterology training for the vast majority of UK trainees, and integral to this is the practice of safe sedation. The majority of endoscopic procedures are performed with the patient under conscious sedation with a benzodiazepine, often combined with an opioid. Little data exists on the practice of sedation among gastroenterology trainees, including their degree of knowledge of the common sedation agents used and their actions. Using both an online and paper-based questionnaire, we surveyed current gastroenterology speciality trainees (ST) in the UK and received 78 responses giving a response rate of 10%. Fifty-one per cent of the trainees did not receive structured training in safe sedation, despite national guidelines advising this to be an essential part of the training programme, and 92% felt a structured sedation course would be beneficial. We also identified some gaps in trainees' knowledge of the action of sedation agents. We propose that a formal training session in sedation or an e-learning module could be incorporated as part of a deanery or trust induction for gastroenterology trainees and kept under regular review.