The Efficacy of Prophylactic TAF for HBsAg-positive Patients Receiving bDMARDs

Phase 4

Not yet recruiting

• Conditions: HBV; Inflammatory Arthritis
• Interventions: Drug: Tenofovir alafenamide

• Registration Number: NCT05001672
• Lead Sponsor: Taipei Veterans General Hospital, Taiwan

Brief Summary

Hepatitis B virus reactivation (HBVr) is an emerging issue and a potentially life-threatening complication to patients with history of Hepatitis B virus (HBV) infection whose immune system is deficient or suppressed. It is estimated that the risk of HBVr ranges 20%-50% in hepatitis B surface antigen (HBsAg)-positive patients undergoing chemotherapy or immunosuppressive therapy. Not only HBsAg-positive patients but also HBsAg-negative/antibody to hepatitis B core antigen (anti-HBc)-positive patients (resolved hepatitis B) have the risk of HBVr.

Recent studies also reported that the risk of HBVr associated with TNF-α inhibitor treatment widely ranged from 12.3% to 62.5%. Antiviral prophylaxis by nucleos(t)ide analogues (NUCs) is recommended for patients with high risk of HBVr according to 2018 AASLD guidance. Phase 3 studies reported that tenofovir alafenamide (Vemlidy, TAF) can effectively suppress HBV in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients, and TAF is superior to TDF in safety profiles and ALT normalization. However, the evidence of TAF in prevention HBV reactivation for patients with HBsAg-positive and imflammatory arthritis, who need bDMARDs are still missing.

Detailed Description

Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. There are up to 248 million people worldwide chronically infected with HBV. HBV reactivation (HBVr) is an emerging issue and a potentially life-threatening complication to patients with history of HBV infection whose immune system is deficient or suppressed. It is estimated that the risk of HBVr ranges 20%-50% in hepatitis B surface antigen (HBsAg)-positive patients undergoing chemotherapy or immunosuppressive therapy. Not only HBsAg-positive patients but also HBsAg-negative/antibody to hepatitis B core antigen (anti-HBc)-positive patients (resolved hepatitis B) have the risk of HBVr. The investigator's studies have demonstrated that the risk of HBsAg seroreversion was 10% in diffuse large B cell lymphoma patients undergoing anti-CD20 (rituximab) treatment; and the risk of HBsAg reverse seroconversion in rheumatic arthritis (RA) patients with resolved HBV infection and received biological disease-modifying antirheumatic drugs (bDMARDs) or glucocorticoid (GC) treatment can persist for up to 10 years. In the investigator's previous study, it also be investigated the risk of HBVr under different immunosuppressant regimens in HBsAg-positive patients with RA, and the investigator pointed out immunosuppressive treatment with a combination of GC, synthetic disease-modifying antirheumatic drugs (sDMARDs), and bDMARDs has the highest risk of HBVr with annual incidence around 20%. Recent studies also reported that the risk of HBVr associated with TNF-α inhibitor treatment widely ranged from 12.3% to 62.5%.

Antiviral prophylaxis by nucleos(t)ide analogues (NUCs) is recommended for patients with high risk of HBVr according to 2018 AASLD guidance. Phase 3 studies reported that tenofovir alafenamide (Vemlidy, TAF) can effectively suppress HBV in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients, and TAF is superior to TDF in safety profiles and ALT normalization. However, the evidence of TAF in prevention HBV reactivation for patients with HBsAg-positive and imflammatory arthritis, who need bDMARDs are still missing. Therefore, the investigator plans to conduct this randomized controlled trial to confirm the efficacy of TAF as a prophylactic antiviral agent for HBsAg-positive patients with inflammatory arthritis (IA) on bDMARDs treatment.

Study Timeline

• Study First Submitted: 2021-07-02
• Status Verified: 2021-08
• Study First Submitted QC: 2021-08-05
• Last Update Submitted: 2021-08-05
• Study First Posted: 2021-08-12
• Last Update Posted: 2021-08-12
• Study Start: 2021-08-15
• Primary Completion: 2025-06-30
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 108

Inclusion Criteria

• Age >=20 years old;
• History of chronic hepatitis B with HBsAg-positive;
• Both HBeAg-positive and HBeAg-negative are allowed;
• Inflammatory arthritis (including psoriatic arthritis);
• On bDMARDs treatment or will start bDMARDs within in 4 weeks. The bDMARDs included all anti-TNF-α agents, rituximab (anti-CD20 monoclonal antibody), tocilizumab (anti-interleukin 6 receptor monoclonal antibody), abatacept (cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin), and all new biologics with indication of IA treatment;
• No NUCs treatment in recent 6 months;
• No limitation of the baseline HBV DNA level;
• Total bilirubin level <2 mg/dL;
• ALT < 2x ULN (<80 U/L).

Exclusion Criteria

• Child-Pugh class >B7;
• Active EV bleeding within 4 weeks;
• History of hepatic encephalopathy or intractable ascites;
• Coexist with other primary liver diseases, such as active chronic hepatitis C, hepatitis D, autoimmune hepatitis, or Wilson's disease. (*HCV RNA undetectable is allowed to enroll);
• Active malignancy;
• Pregnant women.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Observation arm	Tenofovir alafenamide	54 patients will be randomized into observation arm initially. These patients will be closely monitored their HBV status (including qHBsAg and HBV DNA) for 48 weeks. TAF 25 mg QD will be initiated for 144 weeks in the presence of HBV reactivation, or after 48 weeks of observation.
TAF arm	Tenofovir alafenamide	54 patients will be randomized into TAF arm\*. TAF 25 mg QD will be initiated 7 days before bDMARDs, and continued for up to 144-weeks. \*for patients received rituximab (anti-CD20 monoclonal antibody) will be enrolled into TAF arm, and TAF 25 mg QD will be initiated 7 days before rituximab, and continued for up to 144-weeks. Max 20 rituximab patients will be recruited.

Primary Outcome Measures

Name	Time	Method
1-year HBV reactivation rate	Up to 1-year	The assessment for the HBV reactivation is by the marker as hepatitis b viral load (unit: IU/ML).

Secondary Outcome Measures

Name	Time	Method
The 1-year virological remission rate	Up to 1-year	The assessment for the HBV reactivation is by the marker as hepatitis b viral load (unit: IU/ML).
The adverse reactions and compliance	Up to 3-years	The assessment for the adverse reactions is by the CTCAE v5.0, and the compliance is by the residual study drug.
Observation of bone mineral density at 48-weeks, 96-weeks, and 144-weeks	Up to 3-years	The assessment for the bone mineral density is by the marker as T-score.
Serial change of renal and liver function	Up to 3-years	The assessment for the renal function is by the markers as serum creatinine (unit: mg/dL), eGFR (unit: 60 mL/min/1.73M\^2) and serum inorganic phosphorus (unit: mg/dL); for the liver function is by the markers as ALT/AST (unit: U/L) and child-pugh score.; The child-pugh score is determined by scoring five clinical measures of liver disease. A score of 1, 2, or 3 is given to each measure, with 3 being the most severe, and the five clinical measures are: total bilirubin (unit: mg/dL), serum albumin (unit: g/dL), prothrombin time (unit: sec), absence/presence of ascites and absence/presence of hepatic encephalopathy. The higher scores mean a worse outcome.
The 1-year HBeAg seroconversion rate	Up to 1-year	The assessment for the HBeAg seroconversion is by the marker as HBeAg (unit: COI).