Achieving WHO target of HCV control in Hong Kong: challenges and strategies.

With the introduction of effective directly acting antiviral agents (DAAs) therapy, control and elimination of hepatitis C virus (HCV) infection is becoming a feasible goal. In Hong Kong, HCV prevalence in general population is 0.3%-0.5% over the past decades. However, like other high-income areas/countries, high prevalence of HCV infection has been found in several population groups, such as people who inject drugs (PWID), patients undergoing dialysis, and human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/ AIDS) patients. Based on the epidemiological study using data retrieved from the Hong Kong HCV Registry from January 2005 to March 2017, the estimated territory-wide diagnosis rate and treatment rate of HCV infection were only 50.9% and 12.4%, respectively. Although these rates was comparable to many developed countries/areas, the performances remained substantially below 90% and 80%, the 2030 targets proposed by World Health Organization (WHO). In recognition of the challenges, the Hong Kong Government set up the Steering Committee on Prevention and Control of Viral Hepatitis (SCVH) which formulated the Hong Kong Viral Hepatitis Action Plan 2020-2024. The Action Plan adopts four key strategies, as described in the WHO framework for global action, namely, awareness, surveillance, prevention and treatment. With the effective implementation of the Action Plan, especially in targeted screening of high-risk populations and more generalized use of the highly efficacious DAAs for all diagnosed HCV subjects, the goals of reducing HCV transmission and HCV-related morbidity and mortality can be achieved in Hong Kong by 2030.

APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.

BACKGROUND & AIM: Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. METHODS: All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. RECOMMENDATIONS: We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.

Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: A prospective four-years follow-up study.

BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) decreases significantly in chronic hepatitis C (CHC) patients with sustained virologic response (SVR) after pegylated-interferon plus ribavirin (PR) or direct-acting antiviral (DAAs) therapy. We follow-up a single cohort of CHC patients to identify risk factors associated with HCC development post-SVR. METHOD: CHC patients with SVR in Beijing/Hong Kong were followed up at 12-24 weekly intervals with surveillance for HCC by ultrasonography and alpha-fetoprotein (AFP). Multivariate Cox proportional hazards regression analysis was used to explore factors associated with HCC occurrence. RESULTS: Between October 2015 and May 2017, SVR was observed in 519 and 817 CHC patients after DAAs and PR therapy respectively. After a median post -SVR follow-up of 48 months, HCC developed in 54 (4.4%) SVR subjects. By adjusted Cox analysis, older age (≥55 years) [HR 2.4, 95% CI (1.3-4.3)], non-alcoholic fatty liver diseases [HR 2.4, 95%CI (1.3-4.2), higher AFP level (≥20 ng/ml) [HR 3.4, 95%CI (2.0-5.8)], higher liver stiffness measurement (≥14.6 kPa) [HR 4.2, 95%CI (2.3-7.6)], diabetes mellitus [HR 4.2, 95%CI (2.4-7.4)] at pre-treatment were associated with HCC occurrence. HCC patients in the DAAs induced SVR group had a higher prevalence of NAFLD as compared with those in the PR induced SVR group, 62% (18/29) vs 28% (7/25), p = 0.026. A nomogram formulated with the above six independent variables had a Concordance-Index of 0.835 (95% CI 0.783-0.866). CONCLUSION: Underlying NAFLD is associated with increased incidence of HCC in chronic HCV patients post-SVR, particularly in those treated with DAA.

Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening.

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.

Effect of COVID-19 on patients with compensated chronic liver diseases.

BACKGROUND AND AIM: Cytokine storm has been reported in patients with coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We examine the incidence of acute on chronic liver failure (ACLF) in COVID-19 patients with pre-existing compensated chronic liver disease (CLD). METHODS: From 20 Jan 2020 to 7 Feb 2020, we studied 140 consecutive COVID-19 patients admitted to either Fuyang Second People's Hospital (FYSPH), Anhui or the Fifth Medical Center of Chinese PLA General Hospital (PLAGH) in Beijing, China. Pre-existing CLD includes those with liver cirrhosis assessed by APRI/FIB-4 score and /or ultrasound; NAFLD as identified by either ultrasound or hepatic steatosis index with significant liver fibrosis and chronic hepatitis B (CHB) or hepatitis C (CHC) infection. The diagnosis, grading of severity and clinical management of COVID-19 patients complied to the guideline and clinical protocol issued by the China National Health Commission. All patients had liver function test at least twice weekly till discharge with full recovery or death. RESULTS: In total, 3 had liver cirrhosis, 6 patients had CHB, 13 had NAFLD with significant liver fibrosis (one also had CHB). On admission, none had liver decompensation. COVID-19 disease progression was significantly less frequent in non-CLD patients (10/118 8.5%) than CLD patients (13/22 59.1%, p < 0.001). One patient with CLD had acute-on-chronic liver failure (ACLF). CONCLUSION: Disease progression is significantly higher in those COVID-19 patients with CLD as compared to those with no CLD. ACLF can also occur in patient with pre-existing compensated CLD who had severe COVID-19.

Prediction for Progression Risk in Patients With COVID-19 Pneumonia: The CALL Score.

BACKGROUND: We aimed to clarify high-risk factors for coronavirus disease 2019 (COVID-19) with multivariate analysis and establish a predictive model of disease progression to help clinicians better choose a therapeutic strategy. METHODS: All consecutive patients with COVID-19 admitted to Fuyang Second People's Hospital or the Fifth Medical Center of Chinese PLA General Hospital between 20 January and 22 February 2020 were enrolled and their clinical data were retrospectively collected. Multivariate Cox regression was used to identify risk factors associated with progression, which were then were incorporated into a nomogram to establish a novel prediction scoring model. ROC was used to assess the performance of the model. RESULTS: Overall, 208 patients were divided into a stable group (n = 168, 80.8%) and a progressive group (n = 40,19.2%) based on whether their conditions worsened during hospitalization. Univariate and multivariate analyses showed that comorbidity, older age, lower lymphocyte count, and higher lactate dehydrogenase at presentation were independent high-risk factors for COVID-19 progression. Incorporating these 4 factors, the nomogram achieved good concordance indexes of .86 (95% confidence interval [CI], .81-.91) and well-fitted calibration curves. A novel scoring model, named as CALL, was established; its area under the ROC was .91 (95% CI, .86-.94). Using a cutoff of 6 points, the positive and negative predictive values were 50.7% (38.9-62.4%) and 98.5% (94.7-99.8%), respectively. CONCLUSIONS: Using the CALL score model, clinicians can improve the therapeutic effect and reduce the mortality of COVID-19 with more accurate and efficient use of medical resources.

Management of COVID-19 in patients after liver transplantation: Beijing working party for liver transplantation.

Annually, around 850 liver transplantation is performed in Beijing, China. Recently, the new coronavirus pneumonia (COVID-19) caused by 2019 novel coronavirus (2019-nCoV) has affected nearly 200 countries worldwide. 2019-nCov can cause severe lung disease, multiple-organ damage, and significant mortalities. Liver transplant recipients, because of long-term oral immunosuppressant effects, may be more susceptible to 2019-nCoV infection and have a worse prognosis than the general population. It is urgent to set up guidelines for the prevention, diagnosis, and treatment of COVID-19 in liver transplant recipients. In this article, we reviewed the clinical aspects of 2019-nCoV infection, characteristics of liver transplant recipients, immunosuppressant usage, and potential drug interactions to provide recommendations to clinical staff managing liver transplant recipients during the COVID-19 epidemic.

Safety and efficacy of eltrombopag plus pulsed dexamethasone as first-line therapy for immune thrombocytopenia.

Current first-line treatments for immune thrombocytopenia (ITP) usually have transient effects and sustained platelet response off therapy remains low. We evaluated whether eltrombopag plus pulsed dexamethasone as first-line therapy can increase the proportion of patients maintaining platelet counts >50 × 109 /l for a prolonged period without further ITP therapy. Treatment consisted of eltrombopag 25-75 mg daily according to platelet response for 12 weeks plus dexamethasone, 40 mg daily for four consecutive days every four weeks for 1-3 courses. Primary endpoint was durable response off therapy defined as maintaining platelet counts >50 × 109 /l for more than six months without further ITP therapy. Fifty ITP subjects were enrolled between November 2014 and March 2019. Out of 46 evaluable subjects, 26 (56·5%) had achieved the primary endpoint. The median platelet counts at six months off-treatment follow-up were 158 × 109 /l. Only two out of 26 responders had relapsed at eight- and nine-month follow-up. The remaining 24 are still maintaining platelet counts >50 × 109 /l, the longest over three years. All subjects tolerated treatment well and no Grade 3 or above adverse effects were reported. Eltrombopag plus pulsed dexamethasone as a first-line therapy could result in durable response off therapy in a significant number of ITP subjects.

Scalable Generation of Mesenchymal Stem Cells from Human Embryonic Stem Cells in 3D.

Human embryonic stem cell (hESC) derived mesenchymal stem cells (EMSC) are efficacious in treating a series of autoimmune, inflammatory, and degenerative diseases in animal models. However, all the EMSC derivation methods reported so far rely on two-dimensional (2D) culture systems, which are inefficient, costive and difficult for large-scale production. HESC, as an unlimited source, can be successively propagated in spheroids. Here, we demonstrate that hESC spheroids can directly differentiate into MSC spheroids (EMSCSp) within 20 days in one vessel without passaging and the system is scalable to any desired size. EMSCSp can further differentiate into osteocytes and chondrocytes in spheres or demineralized bone matrix. EMSCSp also retains immune-modulatory effects in vitro and therapeutic effects on two mouse models of colitis after dissociation. Compared to EMSC differentiated in monolayer, EMSCSp-derived cells have faster proliferation and higher yield and develop less apoptosis and slower senescence. Thus, the 3D differentiation system allows simple, cost-effective, and scalable production of high-quality EMSC and subsequently bone and cartilage tissues for therapeutic application.

Population-Wide Genetic Risk Prediction of Complex Diseases: A Pilot Feasibility Study in Macau Population for Precision Public Healthcare Planning.

The genetic bases of many common diseases have been identified through genome-wide association studies in the past decade. However, the application of this approach on public healthcare planning has not been well established. Using Macau with population of around 650,000 as a basis, we conducted a pilot study to evaluate the feasibility of population genomic research and its potential on public health decisions. By performing genome-wide SNP genotyping of over a thousand Macau individuals, we evaluated the population genetic risk profiles of 47 non-communicable diseases and traits, as well as two traits associated with influenza infection. We found that for most of the diseases, the genetic risks of Macau population were different from those of Caucasian, but with similar profile with mainland Chinese. We also identified a panel of diseases that Macau population may have a high or elevated genetic risks. This pilot study showed that (1) population genomic study is feasible in Asian regions like Macau; (2) Macau may have different profile of population-based genetic risks than Caucasians, (3) the different prevalence of genetic risk profile indicates the importance of Asian-specific studies for Asian populations; and (4) the results generated may have an impact for going forward healthcare planning.

Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial.

BACKGROUND: Patients with myelodysplastic syndrome or acute myeloid leukaemia who are thrombocytopenic and unable to receive disease-modifying therapy have few treatment options. Platelet transfusions provide transient benefit and are limited by alloimmunisation. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts and has preclinical antileukaemic activity. We aimed to assess the safety and tolerability of eltrombopag for the treatment of thrombocytopenia in adult patients with advanced myelodysplastic syndrome, secondary acute myeloid leukaemia after myelodysplastic syndrome, or de-novo acute myeloid leukaemia. METHODS: We did this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial at 37 centres in ten countries in Europe, east Asia, and the Americas. Patients aged 18 years or older who had relapsed or refractory disease or were ineligible for standard treatments; had platelet counts of less than 30 × 10(9) platelets per L; had 10-50% bone-marrow blasts; or were platelet transfusion dependent were randomly assigned (2:1), via a telephone-based interactive voice-response system (GlaxoSmithKline Registration and Medication Ordering System) with a permuted-block randomisation schedule (block size of three), to receive once-daily eltrombopag or matching placebo dose adjusted from 50 mg to a maximum dose of 300 mg. Randomisation was stratified by presence of poor-prognosis (complex) karyotype (presence of at least three abnormalities, or chromosome 7 abnormalities, vs absence) and bone-marrow blast count (<20% vs ≥20%). Patients and study personnel were masked to treatment allocation. The primary endpoint was safety and tolerability, including adverse events, non-haematological laboratory grade 3-4 toxic effects, and changes in bone-marrow blast counts from baseline. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00903422. FINDINGS: Between May 14, 2009, and May 9, 2013, we randomly assigned 98 patients to receive either eltrombopag (n=64) or placebo (n=34). 63 (98%) patients in the eltrombopag group and 32 (94%) patients in the placebo group had adverse events. The most common adverse events were pyrexia (27 [42%] vs 11 [32%]), nausea (20 [31%] vs 7 [21%]), diarrhoea (19 [30%] vs 6 [18%]), fatigue (16 [25%] vs 6 [18%]), decreased appetite (15 [23%] vs 5 [15%]), and pneumonia (14 [22%] vs 8 [24%]). Drug-related adverse events of grade 3 or higher were reported in six (9%) patients in the eltrombopag group and four (12%) patients in the placebo group. Increases in the proportion of peripheral blasts did not differ significantly between groups. Haemorrhage of grade 3 or higher was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. 21 (33%) patients receiving eltrombopag and 16 (47%) patients receiving placebo died while on treatment. No deaths in patients receiving eltrombopag and two deaths in patients receiving placebo were regarded as treatment related. Post-baseline bone-marrow examinations were done in 40 (63%) patients in the eltrombopag group and 17 (50%) patients in the placebo group. The most common reason for no examination was death before the scheduled 3 month assessment. There were no differences between median bone-marrow blast counts or proportions of peripheral blasts between groups. INTERPRETATION: Eltrombopag doses up to 300 mg daily had an acceptable safety profile in patients with advanced myelodysplastic syndrome or acute myeloid leukaemia. The role of eltrombopag in these patients warrants further investigation. FUNDING: GlaxoSmithKline.