Kelvin Long-Yan Lam

Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome

Objective Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. Design Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. Results Subjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria, Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. Conclusions In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. Trial registration number NCT02570477

Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance

BACKGROUND AND AIMS Previous studies suggested spontaneous seroclearance of hepatitis B surface antigen (HBsAg) was still associated with an increased risk of hepatocellular carcinoma (HCC), in patients ⩾50years of age. This study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of gender on HCC. METHODS All chronic hepatitis B patients under medical care in Hospital Authority, Hong Kong who had cleared HBsAg between January 2000 and August 2016 were identified. The age of the patient at HBsAg seroclearance, gender, and subsequent development of HCC were analyzed. RESULTS A total of 4,568 patients with HBsAg seroclearance were identified; 793 (17.4%) were treated by nucleos(t)ide analogues and 60 (1.3%) had received interferon treatment. At a median (interquartile range) follow-up of 3.4 (1.5-5.0)years, 54 patients developed HCC; cumulative incidences of HCC at 1, 3 and 5years were 0.9%, 1.3% and 1.5%, respectively. Age above 50years (adjusted hazard ratio 4.31, 95% confidence interval 1.72-10.84; p=0.002) and male gender (2.47, 1.24-4.91; p=0.01) were two independent risk factors of HCC. Female patients aged ⩽50years (n=545) had zero risk of HCC within 5years of follow-up. Male patients aged ⩽50years (n=769), female patients aged >50years (n=1,149) and male patients aged >50years (n=2,105) had a 5-year cumulative incidence of HCC 0.7%, 1.0% and 2.5%, respectively. Similar findings were observed in patients with spontaneous and antiviral treatment-induced HBsAg seroclearance. CONCLUSIONS Female patients aged 50years or below have zero risk of HCC after HBsAg seroclearance, whereas female patients aged above 50years and all male patients are still at risk of HCC. Lay summary: We investigated 4,568 patients with hepatitis B surface antigen (HBsAg) seroclearance. Female patients aged 50years or below have zero risk of hepatocellular carcinoma (HCC) after HBsAg seroclearance, whereas female patients aged above 50years and all male patients are still at risk of HCC.

Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial

BACKGROUND Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. METHODS For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT00153660. FINDINGS Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3-9·2) in the celecoxib group and 12·3% (8·8-17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23-0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. INTERPRETATION In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. FUNDING The Research Grant Council of Hong Kong.

Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients

BACKGROUND & AIMS It is uncertain if nucleos(t)ide analogue (NA)-induced hepatitis B surface antigen (HBsAg) seroclearance is durable. We investigated the impact of hepatitis B surface antibody (anti-HBs) and duration of consolidation antiviral therapy on the durability of HBsAg seroclearance. METHODS A territory-wide cohort study was conducted using data from the Hospital Authority, Hong Kong. We identified all subjects with positive HBsAg between January 1, 2000 and August 31, 2016. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was confirmed HBsAg seroclearance, defined least two negative HBsAg test results, with the last HBsAg test being negative in patients with chronic hepatitis B (CHB). RESULTS A total of 4,080 CHB patients were included for analysis. In patients with spontaneous HBsAg seroclearance (n=3,563), 1,771 patients (49.7%) had confirmed HBsAg seroclearance and 75 patients (2.1%) had HBsAg seroreversion. In patients with NA-induced HBsAg seroclearance (n=475), 320 patients (67.4%) had confirmed HBsAg seroclearance and 14 patients (2.9%) had HBsAg seroreversion. The five-year cumulative probability of confirmed HBsAg seroclearance was comparable in patients with spontaneous and NA-induced HBsAg seroclearance (88.1% vs. 92.2%; Log-rank test, p=0.964); it was also similar in patients with or without anti-HBs in NA-treated patients (95.4% vs. 95.5%, Log-rank test, p=0.602). HBsAg seroreversion was only observed in 3 (2.0%) patients who had received consolidation therapy for 6-12months and none of those who had received it for ≥12months. CONCLUSIONS NA-induced HBsAg seroclearance is as durable as spontaneous HBsAg seroclearance. NA-treated patients may not need to have positive anti-HBs before stopping treatment. Longer consolidation NA treatment may result in more durable HBsAg seroclearance. LAY SUMMARY We investigated 4,080 patients with hepatitis B surface antigen (HBsAg) seroclearance. HBsAg seroreversion occurred in 2.1% of patients with spontaneous and 2.9% of those with nucleos(t)ide analogues-induced HBsAg seroclearance.

A new screening strategy for varices by liver and spleen stiffness measurement (LSSM) in cirrhotic patients: A randomized trial

Variceal bleeding is a common and life‐threatening complication in patients with cirrhosis. Screening with upper endoscopy is recommended but is uncomfortable to patients. Non‐invasive assessment with transient elastography for liver/spleen stiffness measurement (LSM and SSM) is accurate in detecting varices.

Normal on-treatment ALT during antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B

BACKGROUND & AIMS Recent studies reveal that the rate of normal on-treatment alanine aminotransferase (ALT) appears different for different nucleos(t)ide analogues (NAs); yet its clinical significance is unclear. We aimed to evaluate the impact of normal on-treatment ALT during antiviral treatment with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB). METHODS A territory-wide cohort of patients with CHB who received ETV and/or TDF in 2005-2016 was identified. Serial on-treatment ALT levels were collected and analyzed. Normal on-treatment ALT (ALT-N) was defined as ALT <30 U/L in males and <19 U/L in females. The primary and secondary outcomes were composite hepatic events (including hepatocellular carcinoma) based on diagnostic codes. Patients with hepatic events before or during the first year of antiviral treatment or follow-up <1 year were excluded. RESULTS A total of 21,182 patients with CHB (10,437 with and 10,745 without ALT-N at 12 months after antiviral treatment) were identified and followed for 4.0 ± 1.7 years. Patients with and without ALT-N differed in baseline ALT (58 vs. 61 U/L), hepatitis B virus DNA (4.9 vs. 5.1 log10 IU/ml) and cirrhosis status (8.8% vs. 10.5%). A total of 627 (3.0%) patients developed composite hepatic events. Compared to no ALT-N, ALT-N at 3, 6, 9 and 12 months reduced the risk of hepatic events, after adjustment for baseline ALT and other important covariates, with adjusted hazard ratios (95% CI) of 0.61 (0.49-0.77), 0.55 (0.45-0.67), 0.54 (0.44-0.65) and 0.51 (0.42-0.61) respectively (all p <0.001). The cumulative incidence (95% CI) of composite hepatic events at six years was 3.51% (3.06%-4.02%) in ALT-N and 5.70% (5.15%-6.32%) in the no ALT-N group (p <0.001). CONCLUSIONS Normal on-treatment ALT is associated with a lower risk of hepatic events in patients with CHB receiving NA treatment, translating into improved clinical outcomes in these patients. LAY SUMMARY We investigated 21,182 patients with chronic hepatitis B receiving antiviral treatment. Alanine aminotransferase is a laboratory marker of liver function, with raised levels indicating liver dysfunction and in severe cases hepatitis. Normal on-treatment alanine aminotransferase during the first year of treatment in patients with CHB is associated with a lower risk of hepatic events.

Disease Burden of Clostridium difficile Infections in Adults, Hong Kong, China, 2006-2014

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p<0.001). Our data suggest the need for further surveillance, especially in Asia, which contains ≈60% of the world’s population.

Pharmacological Treatment in Upper Gastrointestinal Bleeding

Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency. Bleeding peptic ulcers account for the majority of causes in patients presenting with AUGIB, whereas variceal bleeding in cirrhotic patients represents a more severe form of bleeding. Endoscopic therapy is the mainstay of treatment in patients with active bleeding, as it achieves hemostasis and improves patient outcomes. Pharmacotherapy is an important adjunct to endoscopic hemostasis. In the management of patients with bleeding peptic ulcers, acid suppression after endoscopic hemostasis reduces rates of further bleeding and interventions. In patients with stable hemodynamics awaiting endoscopy, acid suppression starts ulcer healing and downstages stigmata of bleeding, thereby reducing the need for endoscopic therapy. In managing patients with variceal bleeding, early administration of vasoactive drugs lowers splanchnic blood flow, promotes hemostasis, and makes subsequent endoscopic treatment easier. The use of vasoactive agents and antibiotics have both been shown to reduce mortality. In this review article, strategies of acid suppression therapy for peptic ulcer bleeds, vasoactive agents, and antibiotics for variceal bleeding, together with recent evidence on the use of tranexamic acid in gastrointestinal bleeding, are discussed.

Commentary: how long does one need to fast before a Fibroscan examination?

Liver stiffness measurement (LSM) is a well-validated non-invasive method to assess liver fibrosis in various liver diseases. In chronic hepatitis B, aminotransferase has been shown to be the major factor affecting LSM. 3 Fibroscan has the beauty of being simple and fast; it can be done in an out-patient setting for a large volume of patients throughout the day. Recent data have shown that food intake might affect the LSM. One therefore needs to know how long a patient has to fast before the procedure, particularly when Fibroscan is performed in the middle of the day instead of in the early morning. Three studies showed that food intake increased LSM in chronic hepatitis C and cirrhotic patients and LSM returned to baseline after 3 h. Lemoine and colleagues demonstrated that food intake after a standardised meal increased liver stiffness in patients with chronic hepatitis B and healthy controls. There was 0.9 kPa increased in LSM at 120 min, which might lead to overestimation of liver fibrosis. The reliability of LSM, as measured by the ratio of interquartile range to LSM, was also hampered after a meal – an intriguing finding that requires further validation. In the literature, obesity is the key factor that increases the failure rate and unreliable results of Fibroscan. In our hospital, we have studied 69 chronic hepatitis B patients with undetectable HBV DNA and normal aminotransferases under anti-viral treatment. Each patient had fasting and 4 h post meal, LSM was measured at week 0 and 2, and the results were combined for analysis. The mean LSM at fasting was 6.3 (2.3–21.3) kPa and 4 h post meal was 6.8 (2.1–35.3) kPa (difference 0.5 kPa; P = 0.05). Fibroscan still had a borderline tendency to overestimate the stage of fibrosis after fasting for 4 h (Table 1). In this study, the reliability of LSM was not affected by a meal. Putting all the evidence together, to avoid overestimation of liver fibrosis by Fibroscan, one should probably advise a patient to fast for at least 4 h before the procedure.

On-Treatment Improvement of MELD Score Reduces Death and Hepatic Events in Patients With Hepatitis B-Related Cirrhosis

OBJECTIVES: Antiviral treatment modifies the natural history of chronic hepatitis B (CHB)‐related cirrhosis as reflected by improving Model for End‐Stage Liver Disease (MELD) score over time. We evaluated the impact of on‐treatment change of MELD score on clinical outcomes in patients with CHB‐related cirrhosis. METHODS: Cirrhotic CHB patients who received entecavir and/or tenofovir disoproxil fumarate for at least 6 months in Hong Kong between 2005 and 2016 were identified. The primary outcome was all‐cause mortality; secondary outcomes were hepatocellular carcinoma (HCC), and hepatic events including ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, hepatic encephalopathy, and liver transplantation. RESULTS: We identified 1743 cirrhotic CHB patients. Their mean MELD score decreased from 12.3 ± 5.5 at baseline to 11.0 ± 4.7 at month 6. At a median (interquartile range) follow‐up of 3.9 (1.9‐6.0) years, 290 (16.6%) patients died; 201 (11.5%) developed HCC. Among 1140 patients without prior hepatic events, 150 (13.2%) developed hepatic events. Among 464 patients with baseline MELD score ≥15, the 6‐year cumulative mortality was 72.8, 36.7, and 23.1% for unchanged or increased MELD score, 1‐5 point improvement in MELD score, and >5 point improvement in MELD score at month 6, respectively (log‐rank test, P < 0.001); the corresponding 6‐year cumulative incidence of hepatic events was 52.7, 30.5, and 23.9% in the three subgroups (Grays test, P = 0.004). Patients with MELD score <15 at month 6 had lower risk of mortality and hepatic events (all P < 0.001). CONCLUSIONS: On‐treatment improvement of MELD score correlates with reduced risk of mortality and hepatic events in cirrhotic CHB patients.