Extended use of Prostate Health Index and percentage of [-2]pro-prostate-specific antigen in Chinese men with prostate specific antigen 10–20 ng/mL and normal digital rectal examination

Peter Ka-Fung Chiu,Jeremy Yuen-Chun Teoh,Wai-Man Lee,Chi-Hang Yee,Eddie Shu-Yin Chan,See-Ming Hou,Chi-Fai Ng 대한비뇨의학회 2016 Investigative and Clinical Urology Vol.57 No.5

Purpose: We investigated the extended use of Prostate Health Index (PHI) and percentage of [-2]pro-prostate-specific antigen (%p2PSA) in Chinese men with prostate-specific antigen (PSA) 10–20 ng/mL and normal digital rectal examination (DRE). Materials and Methods: All consecutive Chinese men with PSA 10–20 ng/mL and normal DRE who agreed for transrectal ultrasound (TRUS)-guided 10-core prostate biopsy were recruited. Blood samples were taken immediately before TRUS-guided prostate biopsy. The performances of total PSA (tPSA), %free-to-total PSA (%fPSA), %p2PSA, and PHI were compared using logistic regression, receiver operating characteristic, and decision curve analyses (DCA). Results: From 2008 to 2015, 312 consecutive Chinese men were included. Among them, 53 out of 312 (17.0%) men were diagnosed to have prostate cancer on biopsy. The proportions of men with positive biopsies were 6.7% in PHI<35, 22.8% in PHI 35–55, and 54.5% in PHI>55 (chi-square test, p<0.001). The area under curves (AUC) of the base model including age, tPSA and status of initial/repeated biopsy was 0.64. Adding %p2PSA and PHI to the base model improved the AUC to 0.79 (p<0.001) and 0.78 (p<0.001), respectively, and provided net clinical benefit in DCA. The positive biopsy rates of Gleason 7 or above prostate cancers were 2.2% for PHI<35, 7.9% for PHI 35–55, and 36.4% for PHI>55 (chi-square test, p<0.001). By utilizing the PHI cutoff of 35 to men with PSA 10–20 ng/mL and normal DRE, 57.1% (178 of 312) biopsies could be avoided. Conclusions: Both PHI and %p2PSA performed well in predicting prostate cancer and high grade prostate cancer. The use of PHI and %p2PSA should be extended to Chinese men with PSA 10–20 ng/mL and normal DRE.

Antiviral activity and safety of LB80380 in hepatitis B e antigen–positive chronic hepatitis B patients with lamivudine-resistant disease

Yuen, Man-Fung,Han, Kwang-Hyub,Um, Soon-Ho,Yoon, Seung Kew,Kim, Hye-Ryon,Kim, John,Kim, Chung Ryeol,Lai, Ching-Lung Wiley Subscription Services, Inc., A Wiley Company 2010 Hepatology Vol.51 No.3

<P>We aimed to determine the antiviral activity and safety of a new nucleotide analogue, LB80380, in chronic hepatitis B (CHB) patients with lamivudine-resistant virus. Sixty-five patients with lamivudine-resistant virus were randomized to receive five ascending daily doses (30, 60, 90, 150, 240 mg) of LB80380. LB80380 was given together with lamivudine for the first 4 weeks, followed by 8 weeks of LB80380 monotherapy. This was then followed by 24 weeks of adefovir. Hepatitis B virus (HBV) DNA levels, serology, liver biochemistry, and safety were monitored. The extent of the HBV DNA reduction at week 12 was dose-dependent. The mean reduction from baseline was 2.81, 3.21, 3.92, 4.16, and 4.00 log<SUB>10</SUB> copies/mL for the five ascending dose groups. The dose-proportionate effect was statistically significant (P < 0.001) with a decrease of HBV DNA levels by an average of 1.54 log<SUB>10</SUB> copies/mL for every 1-unit increase in log<SUB>10</SUB> dose of LB80380. In 93.4% of patients, HBV DNA decreased by >2 log<SUB>10</SUB> copies/mL, and 11.5% of patients had undetectable HBV DNA levels (<300 copies/mL) by week 12. HBV DNA suppression was maintained during the 24 weeks of adefovir treatment. Hepatitis B e antigen seroconversion and normalization of alanine aminotransferase were seen in 14.6% and 24.6% of patients, respectively, at week 12; 44.6% of patients experienced mild and self-limiting adverse events, none of which were attributed to the study drug. Conclusion: LB80380 at doses of up to 240 mg is safe, well tolerated, and effective at reducing viral load in CHB patients with lamivudine-resistant virus for a period of 12 weeks. (HEPATOLOGY 2010.)</P>

Update in the Management of Chronic Viral Hepatitis : Update in the Management of Chronic Viral Hepatitis-Chronic Hepatitis B

Man Fung Yuen 대한간학회 2004 Clinical and Molecular Hepatology(대한간학회지) Vol.10 No.5(S)

Functional Cure of Chronic Hepatitis B and Beyond

( Man-fung Yuen ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

In the past two decades, treatment of chronic hepatitis B by antiviral agents primarily targets prolonged HBV DNA suppression leading to normalization of liver biochemistry, regression of liver fibrosis/ cirrhosis and reduction of liver-related complications and mortality. To advance the treatment goal, functional cure of the disease defined by HBsAg seroclearance is now a common approach in the context of novel agents. Functional cure can be achieved spontaneously or under treatment. Studies on the former mode showed that functional cure attains at younger age e.g. younger than 50 years is associated with a significantly lower risk of development of hepatocellular carcinoma and other liver-related events. These beneficial effects are also observed in treatment-induced functional cure. Another beneficial effect would the allowance of cessation of treatment which is otherwise expected to be given long-term. It is because treatment cessation after achieving functional cure is associated with a minimal risk of disease relapse i.e. sustained HBsAg and HBV DNA negativity. However, both spontaneous and treatment induced functional cure occur at a very low rate. It is estimated to be <1% annually and <10% over 5-10 years of treatment respectively. The HBsAg levels and/or its annual log reduction are predictive factors for functional cure. Therefore, novel treatments are actively underway by many clinical trials to enhance the rate of functional cure. They act directly and indirectly to promote immune restoration and to enhance host control on the virus. The former group include toll like receptor agonists, therapeutic vaccines and immune checkpoint inhibitors. The latter group include agents (short interfering RNAs, anti-sense oligonucleotides) silencing viral mRNA transcriptions and hence removing the immune repressive effect exerted by high load of viral antigens, namely HBsAg. Preliminarily promising results have been shown in recent years. It is anticipated that these agents would be successful and phase III studies are warranted.

New Biomarkers of Chronic Hepatitis B

( Man-fung Yuen ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Since HBsAg, HBeAg and HBV DNA have been standardized and used as viral markers for chronic hepatitis B infection for many decades, their profiles are well characterized in the natural history and treatment of the disease. These existing markers have been proven to be useful in the disease outcome prognostication and treatment efficacy. With the profound viral suppressive effects from nucleos(t)ide analogues (NA), their roles are rather limited in reflecting the cccDNA content. In addition, there are also lacks of reliable markers to predicting viral rebound after cessation of long-term NA therapy. In the recent years, measurements of two novel HBV markers have been actively explored, with the aim of providing better correlations with regard to the disease activity and treatment outcome. They are hepatitis B core-related antigen (HBcrAg) and HBV RNA. HBcrAg is a composite measurement of three viral proteins from pre-core/core gene transcription. They are HBcAg, HBeAg and p22cr. It has been found that HBcrAg has a strong correlation with cccDNA level in the liver even in patients with undetectable serum HBV DNA. In addition, it has significance in different scenarios of HBV disease including its reduction in levels during treatment, rates of HBeAg seroconversion, HBsAg seroclearance, development of cirrhosis and HCC, and HBV reactivations from cessation of treatment and from occult HBV infected patients undergoing immunosuppressive therapy. HBV RNA is another new HBV marker being actively investigated. Pregenomic HBV RNA acts as the template for reverse transcription to relaxed circular DNA after encapsidation. HBV RNA is therefore present in all HBV patients. Under normal circumstance, serum HBV RNA levels are lower than that of serum HBV DNA. It has been shown to have good correlations with HBV DNA and cccDNA. The reduction of HBV RNA was shown to predict HBeAg seroconversion in patients receiving Peg-IFN and/ or NA. Novel treatments targeting HBV RNA knockdown had shown decrease in HBV RNA levels. In addition, detectable HBV RNA was associated with a higher chance of HBV relapse after cessation of the NA treatment. The development of measurements of these two new markers would provide more informative resources for clinicians to have better disease prognostication and management for HBV patients.

New Drugs; Pharmacological Advantage and Clinical Impact : A Phase I/IIa, Double-blind, Randomized, Placebo-controlled Trial of a Novel Antiviral Agent, LB80380 in Patients with Chronic Hepatitis B Infection

( Man Fung Yuen ),( John Kim ),( Danny Ka Ho Wang ),( Vincent Wing Shun Ngai ),( John Chi Hang Yuen ),( Ching Lung Lai ) 대한간학회 2004 Clinical and Molecular Hepatology(대한간학회지) Vol.10 No.1(S)

Update in the Management of Chronic Viral Hepatitis-Chronic Hepatitis B

( Man Fung Yuen ) 대한간학회 2004 추계 학술대회 Vol.10 No.5

New and Emerging Treatment of Chronic Hepatitis B

( Man Fung Yuen ) 대한소화기학회 2009 SIDDS Vol.10 No.-

Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice

Yuen, Man-Fung,Lee, Sung-Hack,Kang, Hyang-Mi,Kim, Chung Ryeol,Kim, John,Ngai, Vincent,Lai, Ching-Lung American Society for Microbiology 2009 Antimicrobial agents and chemotherapy Vol.53 No.5

<B>ABSTRACT</B><P>LB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (<I>T</I>max) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean <I>T</I>max of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption.</P>

Long-term Hepatitis B Surface Antigen Profile and Seroclearance after Severe Acute Flares of Chronic Hepatitis B

Hui Ka-Yin,Fung James,Cheung Ka-Shing,Mak Lung-Yi,Seto Wai-Kay,Yuen Man-Fung 거트앤리버 소화기연관학회협의회 2023 Gut and Liver Vol.17 No.2

Background/Aims: Hepatitis B surface antigen (HBsAg) seroclearance remains uncommon in chronic hepatitis B (CHB) infection. During acute flares of CHB (AFOCHB), alanine aminotransferase elevation reflects a mounting immune response toward viral clearance. We hypothesized that severe AFOCHB is associated with a greater quantitative HBsAg (qHBsAg) decline and HBsAg seroclearance rate. Methods: A total of 75 patients with severe AFOCHB with alanine aminotransferase 10× the upper limit of normal were matched to a control group by age and sex in a 1:2 ratio. qHBsAg levels were measured at the time of flare and annually (for both cases and controls) until the last follow-up. Results: The median follow-up times for patients with severe AFOCHB and controls were 8.8 and 10.5 years, respectively. The cumulative rate of HBsAg seroclearance was higher in the severe AFOCHB group than in the control group (11.8% vs 5.0%, p=0.04) despite the former group having a trend of a higher baseline median qHBsAg (3,127 IU/mL vs 1,178 IU/mL, p=0.076). Compared with the control group, the severe AFOCHB group had a greater annual qHBsAg reduction (–242.4 IU/mL/yr vs –47.3 IU/mL/yr, p=0.002). Increasing age (p=0.049), lower baseline qHBsAg (p=0.002), and severe AFOCHB (p=0.014) were independently associated with HBsAg seroclearance. However, the cumulative rate of hepatocellular carcinoma was significantly higher in the severe AFOCHB group than in the control group (15.8% vs 1.9%, p<0.001). Conclusions: Severe AFOCHB was associated with a greater incidence of HBsAg seroclearance and qHBsAg decline. However, it was associated with a higher incidence of hepatocellular carcinoma.