Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Infections

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Hepatitis A

Hepatitis C

Hepatitis

Hepatitis, Chronic

Hepatitis C, Chronic

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Liver Diseases

Gastrointestinal Diseases

Hepatitis, Viral, Human

Virus Diseases

Communicable Diseases

RNA Virus Infections

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Liver Neoplasms

Gastrointestinal Neoplasms

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Flaviviridae Infections

Disease Attributes

Chronic Disease

Chronic Graft Versus Host Disease

Hematinics

All Drugs and Chemicals

Anti-Infective Agents

Liver Extracts

Antiviral Agents

Arm 1 will be divided into 2 groups by randomization according to a 1:1 ratio into:

Group A: Administration of DAA-based treatment after 3 months of complete remission of HCC.

Group B: Administration of DAA-based treatment after 6 months of complete remission of HCC.

Not receiving DAAs after complete remission of HCC and to be kept on follow-up

* Antiviral therapy and treatment duration (12/24 weeks) will be indicated in each patient according to the viral genotype/subtype and the severity of liver disease, in accordance with the EASL Recommendations on Treatment of Hepatitis C 2016.
* HCV-RNA quantification will be assessed by real-time PCR, with a limit of detection (LOD) of15 IU/mL.
* During antiviral treatment, follow-up of the Patients will be monthly by clinical and laboratory evaluation.
* Virological response to DAA-based treatment will be assessed by quantitative HCV-RNA at the end of treatment (EOT) and at 4 and 12 weeks after the EOT, to confirm sustained virological response (SVR).
* SVR12 is defined as undetectable HCV-RNA at week 12 after the EOT.
* Virological failures and early discontinuations of therapy due to adverse events will be also registered.

Administration of DAA-based treatment

Fatma S Abdelbakey, MD

* Unexpected results were published in 2016 showed increased aggressiveness and rates of HCC recurrence after curative treatment of HCC in HCV patients treated by DAAs achieving SVR. On the other hand, the retrospective analysis of ANRS study, did not observe an increased risk of HCC recurrence after DAAs treatment in patients who underwent curative HCC treatment.
* Assess the recurrence rate of HCC in HCV infected patients with prior history of treated HCC who achieved rCR with and without administration of DAAs and assess the effect of its timing.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver, represents more than 90% of primary liver cancers, and is one of the leading cause of cancer-related death worldwide, therefore, it is a major global health problem.

In 2017, it is estimated that 40,710 people in the united states will be diagnosed with liver cancer and intrahepatic duct cancer; 29,200 males and 11,510 females and approximately 28,920 deaths. Incidence rates of HCC are 3 times higher in males than in females.

In Egypt, the estimated number of liver cancer is increasing as it was 29,975 in 2015 and will be 35,320 in 2020, 41,513 in 2025 and 85,471 in 2050. Liver cancer is the most frequent cancer in Egypt as it represents about 24% of all cancers in Egypt.

Cirrhosis is an important risk factor for HCC, and may be caused by chronic viral hepatitis, alcohol, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency, and non-alcoholic fatty liver disease. All causes of cirrhosis may be complicated by carcinogenesis, but the risk is higher in patients with hepatitis infection. Overall, one-third of cirrhotic patients will develop HCC during their lifetime.

Worldwide, approximately 54% of all cases of HCC are associated with hepatitis B virus (HBV) infection, while 31% are due to hepatitis c virus (HCV) infection, while only 15% are associated with other causes.

The prevalence of HCV infection in Egypt is the highest in the world, so its long-term consequences is a major endemic medical health problem in Egypt. The most common HCV RNA genotype in Egypt is genotype 4, representing more than 85% of all HCV cases in Egypt.

The direct acting antivirals (DAAs) are specific to the HCV particle and aim to inhibit viral RNA replication by attacking some of the various enzymes involved in the RNA replication process, thereby inhibiting viral replication, and causing viral eradication (Muir, 2014).

The primary goal of HCV therapy is to cure the infection, i.e. to achieve a sustained virological response (SVR) which defined as undetectable HCV RNA 12 weeks or 24 weeks after treatment completion. More than 95% of patients have SVR using DAAs except for genotype 3 virus in cirrhotic patients where SVR is still insufficient.

In the last decades before the era of DAAs, it was reported that SVR is associated with a reduction in all-cause mortality, liver mortality, and a reduction in the risk of HCC, this was by several meta-analyses which have studied this issue and suggested that SVR is associated with a reduction in the incidence of HCC in the long-term.

However, most of these studies are observational and retrospective and were based on SVR achieved with interferon (IFN) based therapy. Whether the high rates of SVR achieved with new IFN-free regimens reduce the risk of recurrence following resection or ablation of HCC is currently debated.

The success of DAAs against hepatitis C is a major breakthrough in Hepatology. Till now, there are very few data on the benefits of DAA-based antiviral therapy in patients who have already developed HCC, since this specific population have not been included in the pivotal trials.

Unexpected results were published in 2016 showed increased aggressiveness and rates of HCC recurrence after curative treatment of HCC in HCV patients treated by DAAs achieving SVR, one is a multicenter study conducted in Spain, of 58 patients and the other is a single center study, was done in Italy, of 59 patients, recurrences were 28% and 29%, respectively.

These studies were criticized due to the small number of patients, their retrospective character and lack of control arms, nevertheless their observation should be taken as a note of caution and need a larger assessment.

On the other hand, the retrospective analysis of the France REcherche Nord\&sud Sida-vih Hépatites (ANRS) study in France, did not observe an increased risk of HCC recurrence after DAAs treatment, in patients who underwent curative HCC treatment including liver transplantation.

In addition, it was found in the preliminary results of a prospective observational study of HCV-infected patients with HCC given DAAs that there was no HCC recurrence following curative treatment over a median follow-up period of 12 months after DAA use.

Interestingly, it was reported that a decreased HCC incidence in decompensated cirrhotic patients with SVR achieved by DAAs compared to patients without SVR.

The mechanism which explains the high rate of tumor recurrence after DAAs treatment is that microenvironment and viral induced inflammation play an essential role in chronic liver injury and tumor initiation. However, the immune system has also an anti-tumor effect. Thus, there is a complex and fragile equilibrium between a pro tumor and anti-tumor function of the immune system.

Some studies have suggested that DAA treatment could modify natural killer function and expression of interferon response gene. Therefore, the hypothesis is a dysregulation of the anti-tumor response after the sudden decrease of HCV viral load induced by DAAs which promotes tumor recurrence. However, this phenomenon was unlikely to occur in patients who received IFN due to the slowly developing antiviral effect of this cytokine coupled with its immune modulatory and anti-proliferative properties.

However, this mechanism is purely theoretical and no strong preclinical studies support this hypothesis, but the high rate of HCC recurrence after DAA treatments in patients with prior HCC suggests that a close follow-up of these patients remains mandatory as well as a reassessment of these observations in a prospective study.

Recurrence Rate of Hepatocellular Carcinoma After Treatment of Chronic Hepatits C Patients With Direct Acting Antivirals: Randomized Controlled Phase 3 Trial

RECURRENCE RATE OF HEPATOCELLULAR CARCINOMA AFTER TREATMENT OF CHRONIC HEPATITIS C PATIENTS WITH DIRECT ACTING ANTIVIRALS: RANDOMIZED CONTROLLED PHASE 3 TRIAL (CAUTIOUS TRIAL)

To compare the Recurrence Rate of HCC in the two main randomized arms (administration of DAAs "arm 1" and control arm "arm 2")

To assess the effect of timing of administration of DAAs after achieving rCR as regard recurrence rate in the 2 sub-groups of arm 1 (administration of DAAs after 3 months from rCR "group A" and administration after 6 months "group B")

Identifications of predictive factors of HCC recurrence in chronic HCV patients treated with DAAs and achieved SVR.

Ain Shams University

Ph.D Candidate

Liver Cirrhosis

Fatty Liver

Hepatitis B

Hepatitis B, Chronic

Non-alcoholic Fatty Liver Disease

Enterovirus Infections

Picornaviridae Infections

Hepadnaviridae Infections

DNA Virus Infections

Fibrosis

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

Death

Hypoglycemic Agents

Metformin

1000 mg (2x500 mg) at morning and 1000 mg (2x500 mg) at afternoon (2000 mg per day)

Metformin daily during 36 months

2 tablets at morning and 2 tablets at afternoon 4 tablets per day

placebo tablet

Dominique Roulot, MD

Metformin treatment during 36 months could be associated with decreased risk of HCC occurrence and liver related death in patients with compensated HCV cirrhosis and insulinoresistance.

This study is an ancillary of the observational study from the CIRVIR cohort in which more than 1200 patients with compensated HCV cirrhosis are currently included.

participating centers : 26

Hepatocellular carcinoma (HCC) is currently the first cause of death of patients with compensated HCV cirrhosis.Despite progresses,existing therapies are limited in their ability to prevent recurrences. Even diagnosed at early stage, long-term prognosis remains poor due to the high rate of recurrence after local treatments. Liver transplantation the only long-term curative treatment is limited by advanced age, comorbidities or the shortage of the graft It concerns less than 5 % of HCC patients . Therefore, the best approach to reduce mortality remains the reduction of HCC incidence.

Abundant observational studies have related a relation between insulinoresistance occurrence and outcome of many cancers. The level of IR assessed by the HOMA index have been recognized as an independent predictive factor of HCC occurrence in patients with compensated viral C cirrhosis. Metformin, a Type 2 diabetic treatment drug, inhibits hepatic gluconeogenesis and increases the stimulation of the glucose uptake in muscle.

Independently of its' anti diabetic effects, Metformin is credited of anti tumoral, anti oxidant, anti inflammatory, and anti angiogenic properties.

Amount epidemiological and experimental data have demonstrated the anti tumoral and chemopreventive effect of metformin in certain cancers.

From our cohort of patients with compensated HCV cirrhosis and not treated by insulin, we have observed that the level of IR assessed by the HOMA was a strong and independent risk factor of HCC occurrence and liver related death. We have also observed in our cohort of diabetic patients with compensated HCV cirrhosis, that treatment by Metformin was associated with a decreased risk of HCC occurrence and liver related death.

HYPOTHESIS

Treatment with metformin could decreased the HCC occurrence and liver related death or transplantation.

MAIN OBJECTIVE

Evaluation the impact of Metformin treatment on HCC occurrence and liver related death in patients with compensated HCV cirrhosis and Insulinoresistance SECONDARY OBJECTIVE

* Occurrence of decompensation of the cirrhosis (ascite, sepsis, encephalopathy, haemorrhage)
* Evaluation of the treatment tolerance

MAIN CRITERION JUDGMENT

Rate of HCC occurrence or liver related-death or transplantation.

SECONDARY CRITERION JUDGMENT

* Occurrence of decompensation of the cirrhosis (ascite, sepsis, encephalopathy, haemorrhage),
* Tolerance

STUDY ASSESSMENTS

The patient of CIRVIR cohort meeting the inclusion criteria will be invited to participate to this study.

During their next visit, the hepatologist, will give full verbal and written information regarding the objective procedures of the study and the possible benefice and side effects of the treatment. A write informed consent will be obtained from all patients who agree to participate to the study.

The treatment period will begin following randomization. On day M0 baseline measurements will be taken and recorded, and metformin administration will be begun. In order to optimize the treatment tolerance, it will be suggested to the patients to take the pill during or at the end of the lunch. During the first week, the posology of the placebo and metformin will be 500 mg at the breakfast. After, the posology will be increased every week as follow: 500 mg morning and afternoon, then 1000 mg morning and afternoon (2000 mg per day). In case of intolerance, the maximum posology tolerated will be maintained. In fact regarding the primary data of the trial regarding the effect of metformin on colonic polyp, it seems possible that low dose of metformin are potentially active This treatment will continue until the end of the study.

FOLLOW UP

Patients will be seen at one month and followed every 3 months. Clinical evaluation and HCC screening are planed In CIRVIR cohort study, Every 6 months.

Duration of Treatment per patient:

• 36 months

Duration of Trial Recruitment:

• 24 months

PARTICIPATING CENTERS : 26

NUMBER OF SUBJECT

In order to demonstrate a reduction of 40% (HR 0.6) of events under metformin vs placebo with 80% power and 5% two-sided alpha risk, 200 patients per arm are necessary.A sample size reassessment will be made after 50% and 75% of patients included based on predictive power calculation.

We estimated that 5% of patients will not tolerate the treatment in the first month, and that 5% more will be lost to follow or not compliant to treatment during the follow up period. Therefore, the number of patients to be included is 222 patients per group.

STATISTICAL ANALYSIS

Clinical data of all the patients will be prospectively collected in a computerized database

Populations analyzed The main analysis will be based on the intent-to-treat population (ITT) of all randomized patients

In addition an explanatory analysis (PP) of all patients randomized \& treated without major protocol violations/deviations will be carried out. Pre-defined major protocol violations/deviations are:

1. missing data for the primary efficacy endpoints
2. no study drug received
3. violation of inclusion criteria
4. Additional protocol violations will be possibly defined during the blind data review

Statistical tests. Main criterion: rate of HCC occurrence and liver related-death or transplantation.

The cumulative incidence of HCC and liver-related death or transplantation will be compared according to metformin treatment at inclusion using the log-rank test.

In addition, univariate Cox regression models will be used to identify predictive factors of primary endpoint.

For each endpoint, variables with a P value less than 0.10 in the univariate analysis predicting outcomes will be entered into stepwise Cox regression multivariate models. For sensitivity analyses, the incidence of HCC will be also adjusted on usual risk factors. The same models considering competing risks will be tested using the Fine and Gray test.

Secondary criteria : Occurrence of decompensation of the cirrhosis (ascite, sepsis, encephalopathy, haemorrhage).

Comparisons between groups will be performed first in a univariate manner using the χ2 test or the Fisher-exact tests. Multiple logistic regression models will be used to assessed a possible difference between groups when adjusted on parameters known or identified during the study as possibly affecting these outcomes.

Primary Prevention Hepatocellular Carcinoma by Metformin

PRIMARY PREVENTION OF HEPATOCELLULAR CARCINOMA BY METFORMIN IN PATIENTS WITH VIRAL C CIRRHOSIS : PROSPECTIVE MULTICENTER STUDY, RANDOMIZED CONTROL TRIAL. Ancillary Study of the ANRS CO12 CirVir Cohort

ANRS, Emerging Infectious Diseases

Assistance Publique - Hôpitaux de Paris

Antineoplastic Agents

Interferons

Interferon-alpha

Ribavirin

Interferon alpha-2

Antimetabolites

Immunologic Factors

Interferon, pnce per week plus daily ribavirin

interferon-alfa-2b and ribavirin

Tsutomu Chiba, M.D.,Ph.D.

The purpose of this study is to determine whether low-dose peg-interferon plus ribavirin therapy is effective in the prevention of hepatocellular carcinoma (HCC) in patients who had the curative resection of primary HCC.

Low-dose Peg-interferon Plus Ribavirin (IFN/RBV) for Prevention of Hepatocellular Carcinoma (HCC) Recurrence in Patients Who Had Surgery to Remove Primary HCC

Phase 4 Study of Peg-interferon Plus Ribavirin Therapy for Prevention of Hepatocellular Carcinoma

Kyoto University

Associate professor

Substance Related Disorders

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Central Nervous System Depressants

Amino Acids

Ethanol

Bilirubin

N-Methylaspartate

Alanine

Aspartic Acid

In this group there will be patients with the diagnosis of hepatocellular carcinoma, who underwent direct acting antiviral treatment. We will collect both epidemiological (age, gender, comorbidities, alcohol abuse) and clinical data (serum bilirubin, alanine, aspartate aminotransferase, gammaglutamyltransferase, alkaline phosphatase and alpha-fetoprotein level, Child-Pugh and MELD score, imaging tests, liver biopsy and elastography, if performed). The HCV infection and co-infections will be assessed and also the composition of therapy and the response to treatment will be evaluated.

In this group there will be patients with the diagnosis of hepatocellular carcinoma, who were not receiving direct acting antiviral treatment. We will collect both epidemiological (age, gender, comorbidities, alcohol abuse) and clinical data (serum bilirubin, alanine, aspartate aminotransferase, gammaglutamyltransferase, alkaline phosphatase and alpha-fetoprotein level, Child-Pugh and MELD score, imaging tests, liver biopsy and elastography, if performed). The HCV infection and co-infections will also be assessed.

Our observational study will assess the exposure to direct acting antivirals - the specific drugs, dose, duration of the therapy and the effect of the treatment.

Direct Acting Antivirals

Agnieszka J Lembas

BACKGROUND It is estimated that around 71 milion people live with chronic hepatitis C virus (HCV) infection. This may lead to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Liver cirrhosis is considered as one of the most common risk factors of hepatocellular carcinoma (HCC). HCC is seventh most common cancer worldwide. The treatment of HCV with direct-acting antivirals (DAAs) has led to the increase of sustained virological response (SVR) rates to more than 90%. It is suggested that the virus eradication reduces, but not eliminates the risk of HCC. This concerns especially patients with liver cirrhosis or previous HCC history. There are reports of early occurrence of HCC after the DAA treatment. Therefore, patients undergoing successful HCV treatment should be monitored for the possibility of hepatoccelular carcinoma occurrence.

AIM OF THE STUDY In this study the investigators aimed to assess the occurrence of HCC after direct acting antiviral HCV treatment and evaluate whether the course of HCC and liver function differ among the population of patients treated with DAAs and those who were not receiving the therapy with DAA.

MATERIAL AND METHODS This is the observative, cohort, retrospective study which will be performed in several clinical centres in Poland. The inclusion criteria are: hepatocellular carcinoma diagnosis, age \>18 years old.

The investigators will collect both epidemiological (age, gender, comorbidities, alcohol abuse) and clinical data (serum bilirubin, alanine, aspartate aminotransferase, platelets, gammaglutamyltransferase, alkaline phosphatase and alpha-fetoprotein level, Child-Pugh and MELD score, imaging tests, liver biopsy and elastography, if performed).

In all patients, the HCV infection and co-infections will be assessed. In those who underwent the DAA treatment, the composition of the therapy and response to the treatment will be evaluated.

Statistical analysis will be performed in subgroups of patients undergoing DAA treatment and without the therapy. The distribution of continuous variables will be analysed by the Shapiro-Wilk test. Quantitative data will be analysed using the Mann-Whitney U test or Kruskal-Wallis ANOVA when appropriate. Qualitative data will be compared using the χ² test or the Fisher exact test. Correlations between quantitative variables will be assessed using the Spearman correlation coefficient. P value will be set at \<0.05.

FUNDING:

No remuneration is provided for participation in the study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Recurrence Rate of Hepatocellular Carcinoma After Treatment of Chronic Hepatits C Patients With Direct Acting Antivirals: Randomized Controlled Phase 3 Trial	NCT03551444	Hepatocellular ... Hepatitis C, Ch...	Administration ...	18 Years -	Ain Shams University
Recurrence Rate of Hepatocellular Carcinoma After Treatment of Chronic Hepatits C Patients With Direct Acting Antivirals: Randomized Controlled Phase 3 Trial	NCT03551444	Hepatocellular ... Hepatitis C, Ch...	Administration ...	18 Years -	Ain Shams University
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
Primary Prevention Hepatocellular Carcinoma by Metformin	NCT02319200	Hepatocellular ... Hepatitis C, Ch... Cirrhosis	Metformin placebo tablet	18 Years - 77 Years	Assistance Publique - Hôpitaux de Paris
Low-dose Peg-interferon Plus Ribavirin (IFN/RBV) for Prevention of Hepatocellular Carcinoma (HCC) Recurrence in Patients Who Had Surgery to Remove Primary HCC	NCT00375661	Hepatitis C, Ch...	interferon-alfa...	25 Years - 75 Years	Kyoto University Hospital
Possible Differences in HCC Course Depending on DAA Treatment	NCT05376943	Carcinoma, Hepa... Hepatitis C Vir... Drug Effect Drug Side Effec... Hepatitis C, Ch... Liver Cirrhosis	Direct Acting A...	18 Years - 90 Years	Medical University of Warsaw

Spots Global Cancer Trial Database for hepatitis c, chronic