Michelle C.M. Cheung

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis

BACKGROUND & AIMS All oral direct acting antivirals (DAAs) effectively treat chronic hepatitis C virus (HCV) infection, but the benefits in advanced liver disease are unclear. We compared outcomes in treated and untreated patients with decompensated cirrhosis. METHODS Patients with HCV and decompensated cirrhosis or at risk of irreversible disease were treated in an expanded access programme (EAP) in 2014. Treatment, by clinician choice, was with sofosbuvir, ledipasvir or daclatasvir, with or without ribavirin. For functional outcome comparison, untreated patients with HCV and decompensated cirrhosis who were registered on a database 6months before treatment was available were retrospectively studied. Primary endpoint was sustained virological response 12weeks post antiviral treatment (treated cohort) and the secondary endpoint (both cohorts) was adverse outcomes (worsening in MELD score or serious adverse event) within 6months. RESULTS 467 patients received treatment (409 decompensated cirrhosis). Viral clearance was achieved in 381 patients (81.6%) - 209 from 231 (90.5%) with genotype 1 and 132 from 192 (68.8%) with genotype 3. MELD scores improved in treated patients (mean change -0.85) but worsened in untreated patients (mean+0.75) (p<0.0001). Patients with initial serum albumin <35g/L, aged >65 or with low (<135mmol/L) baseline serum sodium concentrations were least likely to benefit from therapy. CONCLUSIONS All oral DAAs effectively cured HCV in patients with advanced liver disease. Viral clearance was associated with improvement in liver function within 6months compared to untreated patients. The longer term impact of HCV treatment in patients with decompensated cirrhosis remains to be determined.

Outcomes after successful direct acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

BACKGROUND & AIMS Direct-acting antivirals have become widely used for patients with chronic hepatitis C virus infection with decompensated cirrhosis. Virological responses are excellent and early improvements in liver function, at least in a proportion of patients, have been observed but the longer term impact of viral clearance on end-stage liver disease complications is unclear. METHODS Prospective study of patients with decompensated cirrhosis who received 12weeks of all-oral direct-acting antivirals through the English Expanded Access Programme. Endpoints were deaths, liver transplantation, hepatocellular carcinoma, serious decompensation events, sepsis or hospitalisations, and MELD scores between start of therapy to 15months post-treatment start. An untreated cohort of patients was retrospectively studied over 6months for comparison. RESULTS Amongst 317/406 patients who achieved sustained virological response at 24weeks post-treatment, there were 9 deaths (3%), 17 new liver cancers (5%), 39 transplantations (12%) and 52 with serious decompensations (16%), over 15months. When compared to the first six months from treatment start and to untreated patients, there was a reduction in incidence of decompensations [30/406 (7%) in months 6-15 and 72/406 (18%) in months 0-6 for treated patients vs. 73/261 (28%) in untreated patients]. There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6-15 and 17/406 (4%) in months 0-6 for treated patients vs. 11/261 (4%) in untreated patients). CONCLUSIONS This study suggests that antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy. LAY SUMMARY This is a report of a large group of patients in England who have hepatitis C virus (HCV) infection with advanced liver disease. They have been treated with new anti-HCV drugs, which cured the infection in the majority. This study looks at their outcomes a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that in most patients anti-HCV treatment is beneficial even in advanced liver disease.

Human CHN1 Mutations Hyperactivate α2-Chimaerin and Cause Duane's Retraction Syndrome

Duanes retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes α2-chimaerin, a Rac guanosine triphosphatase–activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase α2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance α2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant α2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that α2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

Human CHN1 Mutations Hyperactivate α2-Chimaerin and Cause Duanes Retraction Syndrome

Duanes retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes α2-chimaerin, a Rac guanosine triphosphatase–activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase α2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance α2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant α2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that α2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

Hepatitis E--an unexpected problem at home.

While viral hepatitis in Europe has mainly focused on hepatitis B and C, there is emerging evidence to suggest that hepatitis E is an overlooked sporadic infection in industrialized countries. In the UK, France and Japan for instance, it is more common than hepatitis A infection, occurring in patients without foreign travel. The incidence of autochthonous hepatitis E virus (HEV) infection is uncertain. Moreover, HEV in developed countries affect the middleaged to elderly and is associated with higher mortality than endemic infection. HepatitisEcanmanifestwithextrahepatic symptoms. We report a 56-year-old Caucasian who presented with acute upper limb pain andweakness. Incidental finding of elevated transaminase (AST 234 IU/l, bilirubin 30 mmol/l) led to the discovery of HEV IgM antibodies and positive HEV viral titer. There was no obvious risk factor for acquiring infectionapart fromconsumptionof porksausage,swinereservoir isthoughttoberesponsible for locally acquired cases in developed countries. Within 1 week the liver enzyme derangement normalized and serum clearance of virus occurred by 6 weeks. However, the patient experienced ongoing limb pain 10 months following HEV infection. The neurological deficit was consistent with brachial neuritis, one of the commonest forms of neuropathy associated with HEV. There are fewer than 20 reports of neurological manifestations of hepatitis E, including those of chronic liver disease in immunocompromised patients. Treatment with immunoglobulin or plasmaphoresis did not produce consistent result in this small population. Thus, it is important to consider hepatitis E when investigating patients with liver injury, who may otherwise be diagnosed as drug-related or seronegative hepatitis. It is also obsolete to think of HEV only as an infection causing acute hepatitis in developing countries [1].

Acute liver toxicity with ifosfamide in the treatment of sarcoma: a case report

IntroductionIfosfamide is a chemotherapy agent infrequently associated with liver toxicity. To the best of our knowledge, this report is the first to describe serious liver toxicity associated with ifosfamide used in combination with doxorubicin that caused acute but fully reversible liver failure and encephalopathy. This report reviews the possible mechanisms by which ifosfamide causes this adverse effect.Case reportA 61-year-old Caucasian woman who presented with an inoperable right neck mass due to synovial sarcoma was treated with standard-dose ifosfamide and doxorubicin. Within 24 hours of completing the first cycle of chemotherapy, she developed significant derangements in liver function, with a 250-fold increase in transaminase and associated synthetic function impairment and encephalopathy. No other causes of liver failure were identified. Both biochemical tests and encephalopathy were reversed after supportive management and treatment with N-acetylcysteine. No liver toxicity was observed with subsequent cycles of chemotherapy with doxorubicin alone.ConclusionThis case highlights the possibility that chemotherapy agents can cause rare and idiosyncratic toxicities, so physicians must be vigilant for drug reactions, especially when patients do not respond to usual treatment.

Liver abnormalities in the immunosuppressed

The immunosuppressed state may arise due to medical illness or drug therapy, which can result in a diverse array of liver derangements. This article discusses the commonly-encountered immunosuppressed conditions and the associated specific liver diseases. Due to the frequency of blood-borne viral disease globally, viral hepatitis (hepatitis B and C) during chemotherapy, transplantation and the increasingly utilised biological therapies for autoimmune disorders is discussed. An overview of human immunodeficiency virus co-infection with hepatitis B and C is provided. This article aims to highlight the variety of liver diseases which can occur in clinically relevant, particularly iatrogenic, immunosuppressed conditions, and summarise learning and practice points for clinicians. Recognition and prevention of viral liver disease is crucial and early involvement of experts prior to administration of immunosuppressive therapy is advised.

Antiviral treatment in patients with advanced hepatitis C virus cirrhosis with sofosbuvir and either ledipasvir or daclatasvir, with or without ribavirin: observational cohort study

Abstract Background Direct acting antivirals (DAAs) successfully clear hepatitis C virus (HCV) infection without the use of interferon, allowing treatment of patients with advanced liver disease. Since April 2014, the Expanded Access Program (EAP) in England has provided DAAs for patients with advanced HCV cirrhosis—namely, sofosbuvir with ledipasvir or daclatasvir. We aimed to study the effectiveness of DAAs in advanced HCV cirrhosis, and to see whether viral clearance results in early liver function change. Methods We included patients with advanced HCV liver disease fulfilling NHS England EAP criteria, who received 12 weeks of sofosbuvir and either ledipasvir or daclatasvir, with or without ribavirin (clinicians were free to choose the regimen). Patients were enrolled in the HCV Research UK database, and they consented to prospective data collection between April 1, 2014 (start of EAP), and Nov 11, 2014. A control group of patients with untreated HCV advanced cirrhosis was selected retrospectively between Oct 5, 2012, and Sept 11, 2014 (at least 6 months before EAP start), from the same database. Outcomes were sustained virological response (HCV RNA Findings Our cohort consisted of 467 treated patients (mainly HCV genotype 1 [n=231] and genotype 3 [n=192] infections) and 261 controls. 409 (88%) of 467 patients had past or present decompensation, and median MELD score was 11 (predicted 3 month mortality 6%). Significantly more patients with genotype 1 than genotype 3 infection achieved SVR12 (209 [91%] vs 132 [69%], p vs 28% [73/261], p=0·0006). All-cause adverse outcomes (MELD increase ≥ 2 and any serious adverse event) were reduced (52% [214/409] vs 64% [166/261], p=0·004) but there was no significant difference in incidence of primary liver cancer, sepsis, or death. Interpretation High viral response rates were achieved with 12 weeks of treatment with DAAs in this large real-life patient cohort with advanced cirrhosis, who previously had limited treatment options. Patients with genotype 3 disease remain difficult to cure with existing regimens. That HCV treatment was associated with early improvements in liver function is clinically relevant in a population with poor prognosis. The longer-term impact of HCV treatment in patients with advanced cirrhosis needs to be determined. Funding NHS England, Gilead, Bristol-Myers Squibb, HCV Research UK.