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Diagnosis of Hepatitis B related liver disease in a pre-advanced stage

Diagnosis of advanced liver disease related to Hepatitis B

MahmoudReza Pourkarim, PhD

In this project proposal, the investigators will investigate the genetic alterations of Hepatitis B Virus (HBV) strains circulating in Belgian patients who developed end stage liver disease. Additionally, the investigators will compare and link these data sets with three genetic factors involved in immune system response.

This project proposes to identify and characterize the genetic alterations associated with intra-host evolution of HBV from a chronically infection status to an end-stage liver disease status.

Assessment of Hepatitis B Virus Intra-host Population and Host-specific Immune Marker Diversity

Assessment of Hepatitis B Virus Intra-host Population and Host-specific Immune Marker Diversity With Next-generation Sequencing: From Chronic Infection to End-stage Liver Disease and Liver Cancer

Virus variants will be identified by amino acid or nucleotide variations (insertions or deletions) in different Open Readind Frames (ORFs) of the HBV genome by using next-generation sequencing.

Comparison of virus variants within one patient Comparison of virus variants between patients with end stage liver disease and patients with a chronic Hepatitis B infection.

Determination of the viral load by quantitative Polymerase Chain Reaction (PCR).

Amplification of HLA-A, HLA-B, HLA-C class I and HLA class II using PCR methods and next-generation sequencing

Amplification of KIR genes: 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1 and 1D, 2DL1 2DL2, 2DL3, 2DL5 and 3DL1 using PCR methods and next-generation sequencing

Amplification of SNPs in TNF alfa, TGF beta1 and IFN-R using PCR methods and next-generation sequencing

Fund for Scientific Research, Flanders, Belgium

Universitaire Ziekenhuizen KU Leuven

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Liver Cirrhosis

Fibrosis

Acquired Immunodeficiency Syndrome

HIV Infections

Anti-Infective Agents

Tenofovir

Antiviral Agents

Reverse Transcriptase Inhibitors

Enzyme Inhibitors

Anti-HIV Agents

Anti-Retroviral Agents

Patients whose viral load, ALT value and fibrosis status does not meet EASL criteria for treatment and are observed 6 monthly

Patients who meet EASL treatment criteria who receive Tenofovir disoproxil

Tenofovir disoproxil

Mark Thursz, MD FRCP

The West African Treatment Cohort for Hepatitis B (WATCH) study is a component of the European Commission Funded FP7 project PROLIFICA. It aims to evaluate a number of steps required to successfully treat patients with chronic hepatitis B virus infection to prevent cirrhosis and liver cancer. The first step is to determine whether screening for hepatitis B using a point of care test is feasible and effective. The second is to monitor linkage from screening into care. The third is to evaluate cheap non-invasive assessments to determine the need for treatment. The fourth is to determine what proportion of patients meet treatment eligibility criteria. The fifth step is to establish a treatment cohort which can be used to measure adherence to therapy and avoidance of HBV related complications. A parallel untreated cohort will be established to determine whether treatment criteria are relevant in this West African setting by monitoring for complications of HBV infection.

Objectives Primary:

To determine whether suppression of HBV with a nucleotide analogue reduces the risk of liver cancer in West African populations.

Secondary:

To demonstrate that HBV replication can be effectively suppressed with a nucleotide analogue in West African populations To evaluate whether European treatment guidelines are applicable in West Africa To establish the applicability and efficacy of population based screening, clinical assessment and treatment in West Africa To enumerate the proportion of the adult population who carry HBV To evaluate the proportion of the HBV infected population who meet European Association for Study of the Liver (EASL) criteria for treatment

Endpoints Primary:

Incidence of Hepatocellular Carcinoma over the period of study in a treated cohort of patients with chronic HBV compared to historical controls

Secondary:

Proportion of adult population in Gambia and Senegal with chronic HBV infection Proportion of patients with chronic HBV infection who meet EASL treatment criteria Proportion of patients with undetectable HBV DNA \< 400 copies/ml at 1, 2, 3, 4 and 5 years of treatment.

Incidence of hepatocellular Carcinoma in patients who do not meet EASL treatment criteria.

Treatment adherence rate. Average change in Fibroscan score after 3 and 5 years of treatment Emergence of resistance to treatment

Study Phase 4

Study Design A two part study:

Part 1 - Population based screening for HBV infection using a point-of-care test.

Part 2 - Non-randomised, open label, treatment cohort with parallel observation cohort

Number of Subjects Part 1:

Approximately 13,500 adults from the general population.

Part 2:

300 subjects in the treatment group 600 subjects in the observation group

Study Population Part 1:

Males and females aged over 30 years

Part 2:

Patients with chronic hepatitis B virus infection identified through population based screening.

Treatment Cohort There will be a single treatment group of 300 patients who meet EASL treatment criteria.

Schedule of Study Visits Part 1:

A single visit to an individual at their home or workplace when screening for HBV infection will be performed using a point-of-care test..

Part 2:

One screening visit will be performed to determine viral load, liver function tests, clinical examination, ultrasound examination and liver fibrosis assessment.

A second visit, 1 - 3 months later, will be used to verify viral load and ALT values

For those on treatment cohort:

A baseline visit will take place 2 weeks after the second screening visit and study drug will be dispensed with instructions for the patient.

First follow-up will be at 1 month to check adherence Second follow-up will be at 3 months for viral load and liver functions tests Treatment subjects will be seen every 3 months to dispense study drug and check compliance Viral load, liver function, renal function, AFP and ultrasound will be performed every 6 months.

Serum/plasma and urine samples for biomarkers of cancer development will be taken at baseline and annually.

Population Screening (Part 1 only) Communities will be sensitised about the study prior to visits by fieldworkers to individual homes, places of work or recreational facilities. A point-of-care test based on the detection of hepatitis B surface antigen (HBsAg) in a finger-prick blood sample will be used for screening. Subjects with a positive test will be given a hospital appointment for full clinical assessment.

Efficacy Evaluations (Part 2 only) Detection of liver cancer - Surveillance for liver cancer will be made using ultrasound and serum AFP every 6 months on all subjects. In some centres further imaging will be available.

Liver cancer will be diagnosed according to the following criteria:

* Liver mass with typical features of hepatocellular carcinoma on two imaging modalities (ultrasound, bubble ultrasound or CT), or
* liver mass on ultrasound and AFP \> 400 iu/ml or
* histological or cytological confirmation of diagnosis.

Viral Load - viral load will be measure on EDTA plasma samples using an in-house real-time PCR assay verified for accuracy against commercial assays every 6 months.

Safety Evaluations (Part 2 only) Liver function tests, serum phosphate and renal function will be tested every 6 months

Evaluation of treatment guidelines Subjects who do not meet the EASL treatment criteria at baseline will be enrolled in the observational study with surveillance for liver cancer every 6 months

Detection of viral resistance Viral load monitoring of patients in the treatment study every 6 months will be used to detect possible virological resistance. A rise in viral load from nadir values or reappearance of detectable viraemia in patients who had achieved undetectable viral load will be investigated for emergence of viral sequence variants and for adherence to therapy

PROLIFICA - West African Treatment Cohort for Hepatitis B

Prevention of Liver Fibrosis and Cancer in Africa. Observational Study of Screening, Assessment and Treatment for Chronic Hepatitis B Virus Infection

Sensitivity and specificity of capillary blood sample HBsAg test applied at point of care

Sensitivity, specificity and ROC analysis of Fibroscan, APRI and FIB4 tests compared to liver biopsy to assess liver fibrosis

Subjects will be reviewed 6 monthly with liver biochemistry and ultrasound to detect onset of hepatocellular carcinoma or decompensated cirrhosis

Proportion of community subjects who accept screening tests

Proportion of patients who test positive for HBsAg

Proportion of patients who test positive for HBsAg who attend clinic for assessment

Proportion of patients with HBsAg who meet EASL treatment criteria

Medical Research Council Unit, The Gambia

Department of State for Health and Social Welfare, The Gambia

UFR Sante de Thies, Senegal

Cheikh Anta Diop University, Senegal

Institut National de la Santé Et de la Recherche Médicale, France

International Agency for Research on Cancer

Imperial College London

Fatty Liver

Hepatitis C

Non-alcoholic Fatty Liver Disease

Hepatitis C, Chronic

Flaviviridae Infections

Visceral Steatosis

Follow up every 3 months for liver cancer surveillance, including but not limited to serum AFP test and ultrasound exam

Liver cancer surveillance every 3 months

Follow up every 6 months for liver cancer surveillance, including but not limited to serum AFP test and ultrasound exam

Liver cancer surveillance every 6 months

Follow up annually for liver cancer surveillance, including but not limited to serum AFP test and ultrasound exam

Liver cancer surveillance annually

Qing Xie, MD

Honglian Gui, MD,PhD

Qing Xie, MD, PhD.

The goal of this study is to evaluate whether the standardized liver cancer risk stratification management can effectively improve the early diagnosis rate of liver cancer in the targeted risk population in China.

Digitalized Surveillance Management for Liver Cancer Risk Population in Improving Eearly Diagnosis Efficancy in Chinese Population (dSEARCH)

Exploration of A Holistic Management Procedure for Liver Cancer Surveillance in Improving Liver Cancer's Early Diagnosis Efficacy in Chinese Population: Single-Center, Prospective, Observational Real-world Study in EASTERN China

The disease types include but are not limited to hepatitis B, hepatitis C, cirrhosis, MAFLD

The disease types include but are not limited to hepatitis B, hepatitis C, cirrhosis, MAFLD; early diagnosis of HCC is defined as the patient with stage CNLC Ia, Ib and IIa

The compliance rates for subjects with very high-risk, high-risk, medium-risk, and low-risk; the compliance rate is defined the same as above

The proportion of patients who are first diagnosed with HCC at early stage to all the patients diagnosed as liver cancer in the study, from the start of the study to the completion of follow-up. Early diagnosis is defined as the patient with stage CNLC Ia, Ib and IIa.

Regular follow-up is defined as the average difference between the actual treatment time and the theoretical treatment time equal or less than 1/3

* Actual visit interval: actual visit date - previous visit date ② Theoretical visit interval: theoretical visit date (the date that physician advise to return to hospital for visit) - previous visit date ③ Follow-up compliance = (②-①)/② ④ Patient with regular follow-up is defined as the patient whose mean follow-up compliance is equal to, or less than 1/3

  * The compliance of the study is defined as the proportion of subjects with regular follow-up to all subjects in the study.

The proportion of very high-risk, high-risk, medium-risk, and low-risk subjects to the whole subject population

The proportion of very high-risk, high-risk, medium-risk and low-risk subjects to the whole subject population

The early diagnosis rate of liver cancer of subjects with very high-risk, high-risk, medium-risk, and low-risk at initial screening, respectively

The 3-year cumulative incidence of liver cancer for subjects with very high-risk, high-risk, medium-risk, and low-risk, respectively

Ruijin Hospital

Director of Department of Infectious Diseases, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Entecavir

CHB patients with entecavir naive treatment

CHB patients with naive tenofovir disopropyl naive treatment

entecavir naive for chronic hepatitis B patients

tenofovir disopropyl naive for chronic hepatitis B patients

Tenofovir Disoproxil

The current first-line treatment for HBV is long-term oral antiviral drugs to inhibit HBV DNA replication. First-line antiviral drugs recommended by the Chinese 2015 Hepatitis B Guidelines include ETV and TDF. This study is based on a real-world clinical cohort to retrospectively analyze the effects of ETV and TDF on the long-term (5-year) incidence of HCC in Chinese patients with chronic hepatitis B with compensated cirrhosis. The results will guide the revision of the Chinese HBV guidelines.

HBV infection is a global problem, and China has a heavy disease burden with approximately 86 million people infected with HBV. According to the epidemiological survey of nearly 230,000 people in Northeast China in 2010-2013, the positive rate of HBsAg reached 6.1%, of which 10.7% had cirrhosis.

According to the latest authoritative guidelines, including the guidelines published in 2018 by American Association for the Study of Liver Diseases (AASLD) and in 2017 by European Association for the Study of Liver Diseases (EASL), entecavir (ETV) and tenofovir diisopropyl (TDF) are recommended as first-line antiviral drugs. ETV is a guanosine nucleoside analog that inhibits HBV polymerase and inhibits the synthesis of HBV DNA. TDF is a cyclic nucleoside phosphorylated diester structural analog of adenosine monophosphate, and its hydrolysis and phosphorylation products can inhibit the activity of HBV reverse transcriptase and also inhibit the synthesis of HBV DNA. In 2005, ETV was listed in China Mainland and TDF was listed in 2014. Over the years, clinical studies have shown that both have good antiviral effects and low drug resistance rates, so they are chosen as first-line antiviral drugs.

HBV infection is one of the risk factors for hepatocellular carcinoma (HCC). Previous studies based on the Chinese patients have shown that antiviral therapy (such as ETV) can significantly reduce the incidence of HCC in patients with cirrhosis (the 4-year cumulative incidence of HCC decreased from 17.5% to 9.4%). However, a study from South Korea published online in September 2018 in JAMA Oncology showed that TDF significantly reduced the incidence of HCC compared to ETV (HR 0.68, 95% CI 0.46-0.99) . In contrast, another multicenter study in Korea, published in March 2019 in The JOURNAL OF HEPATOLOGY showed no significant difference between ETV and TDF (HR 0.975, p=0.852) \[4\]. In the latter study, there was a problem with the small sample size, and the sample size was not sufficient to test the difference between the two antiviral drugs, and the sample size needed to be expanded to verify the result.

Compared with Koreans, the incidence of HCC in Chinese is significantly lower (in patients with cirrhosis, the 5-year cumulative incidence of HCC is about: China vs Korea: 12% vs 20%), showing the differences between countries. There is at present no similar study based on Chinese patients, especially in patients with cirrhosis to compare the effects of ETV and TDF on the incidence of HCC.

China has a huge disease burden and a high incidence of HCC. The ETV and TDF both have generic drugs marketing in China Mainland which through quality consistency evaluation and entering the 4+7 drug procurement (the centralized drug procurement in "4+7 Cities": Beijing, Tianjin, Shanghai, Chongqing, Shenyang, Dalian, Xiamen, Guangzhou, Shenzhen, Chengdu and Xian), bringing good antiviral effect to patients at preferential prices. If we can detect the difference in the occurrence of HCC between ETV and TDF, rational selection of drugs will reduce the incidence of HCC in Chinese patients with chronic hepatitis B (Korean studies showed that cumulative HCC patients can reduce 32% in 5 years), greatly reducing the burden on Chinese patients and health care.

This research is a real-world, multi-center, retrospective, and observational study.

Patient data are collected from 5-10 research centers in mainland China, including basic demographic information, antiviral regimen, time of stating antivirus, endpoint event, time of endpoint event, last follow-up time, important testing data, etc.

Patients with the time of last follow-up (or the time of the endpoint event) between 2013-1-1 and 2019-12-31 are included in this study.

Based on the data we collect, the Propensity Score Matching and Inverse Probability Multiple Weighted methods and the Competing Risk Model are utilized to correct the confounding factors to calculate the impact of TDF and ETV on HCC events.

Risk of Hepatocellular Carcinoma in Patients Treated With ETV vs TDF for Chronic Hepatitis B With Compensated Cirrhosis

Risk of Hepatocellular Carcinoma in Patients Treated With ETV vs TDF for Chronic Hepatitis B With Compensated Cirrhosis: A Multicenter, Real-world and Respective Study

Compare the difference in the 5-year cumulative incidence of HCC in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.

Compare the difference in the 5-year cumulative all-cause mortality rate in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.

Compare the difference in the 5-year cumulative liver transplantation rate in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.

Compare the difference in the 5-year cumulative liver disease-related mortality in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.

Shanghai MedSci Healthcare Co. Ltd

Qing XIe

Director of Department of Infectious Disease, Rui Jin Hospital

Arm A:Continue TDF 300mg daily for extend 24 weeks after completion of chemotherapy

Arm B: Continue TDF 300mg daily for extend 48 weeks after completion of chemotherapy.

To compare extend TDF 24 wks versus 48 wks prophylaxis efficacy in chemotherapy CHB patients

Chao-Wei Hsu, MD

To evaluate the effectiveness and safety of tenofovir for different treatment duration in preventing HBV relapse in patients with malignancies after receiving chemotherapy and off-treatment of chemotherapy.

This study aims to evaluate the effectiveness and safety of tenofovir in preventing HBV relapse in HBV carriers with malignant tumor following chemotherapy. Approximately 100 patients who are planned to receive chemotherapy for malignant tumor will be invited to participate in this trail. A 1 or less 1-week tenofovir prophylaxis treatment should be administered by all subjects prior to the chemotherapy and eligible subjects will be randomly assigned to extend 24-week prophylaxis group A or 48-week prophylaxis group B in a 1:1 ratio at the end of the chemotherapy. The subjects could be stopped or withdrawn from this study earlier if HBV relapses or need to receive another course of chemotherapy respectively. The relapse episode will be followed until 24 weeks after the end of prophylaxis therapy. Data collection will take place at screening, every cyclic visit of chemotherapy, at the end of chemotherapy, and the following prophylaxis period, then every 4 weeks during the follow-up period. Patients in both groups will be treated with tenofovir or other antiviral agent according to investigator judgement when HBV relapse after discontinuation of tenofovir therapy.

Tenofovir 300mg QD. Two arm: 6 month and 12 month.

Prophylaxis of CHB Patients With Malignant Tumor Receiving Chemotherapy

Phase IV; Different Extend Treatment Duration (6 Months vs 12 Months After Chemotherapy) to Prevent HBV Relapse With Tenofovir for Prophylaxis in Patients With Malignant Tumor Combined With HBV Carrier Receiving Chemotherapy

To compare the HBV relapse rate during the follow-up period in HBV carriers with malignant tumor receiving tenofovir for 24 and 48 weeks after the end of chemotherapy.

\* HBV relapse is defined as: acute liver flare, i.e. ALT ≥ 2 x ULN and HBV DNA \> 2000 IU/mL.

AST, ALT, Bil(T), Cr (eGFR or MDRD), phosphate, urine analysis, HBsAgQT and HBV DNA were measured at baseline, every 2 cycle of chemotherapy, the end of chemotherapy, the end of TDF and the end of complete follow-up (after the end of TDF for 6 months).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Assessment of Hepatitis B Virus Intra-host Population and Host-specific Immune Marker Diversity	NCT02148562	Hepatitis B Hepatitis B, Ch... End Stage Liver... Carcinoma, Hepa...		-	Universitaire Ziekenhuizen KU Leuven
PROLIFICA - West African Treatment Cohort for Hepatitis B	NCT02129829	Hepatitis B, Ch... Hepatocellular ...	Tenofovir disop...	18 Years -	Imperial College London
Assessment of Hepatitis B Virus Intra-host Population and Host-specific Immune Marker Diversity	NCT02148562	Hepatitis B Hepatitis B, Ch... End Stage Liver... Carcinoma, Hepa...		-	Universitaire Ziekenhuizen KU Leuven
Digitalized Surveillance Management for Liver Cancer Risk Population in Improving Eearly Diagnosis Efficancy in Chinese Population (dSEARCH)	NCT05870969	Carcinoma, Hepa... Hepatitis C, Ch... Hepatitis B, Ch... Cirrhosis, Live... Non-Alcoholic F...	Liver cancer su... Liver cancer su... Liver cancer su...	18 Years - 75 Years	Ruijin Hospital
PROLIFICA - West African Treatment Cohort for Hepatitis B	NCT02129829	Hepatitis B, Ch... Hepatocellular ...	Tenofovir disop...	18 Years -	Imperial College London
Risk of Hepatocellular Carcinoma in Patients Treated With ETV vs TDF for Chronic Hepatitis B With Compensated Cirrhosis	NCT04160897	Hepatitis B, Ch... Hepatocellular ... Compensated Cir...	Entecavir Tenofovir Disop...	18 Years - 80 Years	Ruijin Hospital
Prophylaxis of CHB Patients With Malignant Tumor Receiving Chemotherapy	NCT02081469	Hepatitis B, Ch... Tumor	TDF	18 Years - 70 Years	Chang Gung Memorial Hospital

Spots Global Cancer Trial Database for hepatitis b, chronic