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A Study of GSK3228836 in Participants With Chronic Hepatitis B (CHB) (B-Clear)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04449029
Recruitment Status : Recruiting
First Posted : June 26, 2020
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
Chronic hepatitis B virus (HBV) infection is a significant worldwide medical problem. GSK3228836 demonstrated target engagement in CHB participants who were not on treatment and in CHB participants on stable nucleos(t)ide therapy. This study is intended to evaluate if treatment with GSK3228836 can achieve sustained virologic response (SVR), that is hepatitis B virus surface antigen (HBsAg) less than (<) lower limit of quantitation (LLOQ) and HBV deoxyribonucleic acid (DNA) <LLOQ sustained for 24 weeks post-GSK3228836 treatment end. In addition, the study will also evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of GSK3228836 in the 4 dosing regimens. This study will assess the efficacy and safety of treatment with GSK3228836 in two populations of participants with CHB; participants on stable nucleos(t)ide treatment (Cohort 1) and participants who are not currently on nucleos(t)ide therapy (Cohort 2). For each population, participants will be randomized into one of the 4 different parallel arms to receive treatment. The study will consist of a screening, treatment, and post-treatment follow-up phase. Approximately, 440 participants will be enrolled in the study.

Condition or disease Intervention/treatment Phase
Hepatitis B Drug: GSK3228836 Drug: Placebo Drug: Nucleos(t)ide therapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants with CHB will be divided into two different cohorts; participants on stable nucleos(t)ide treatment and participants not currently on nucleos(t)ide therapy. For each cohort, participants will be randomized into one of the 4 different parallel arms to receive treatment.
Masking: Single (Participant)
Masking Description: Participants will be blinded to the study treatment.
Primary Purpose: Treatment
Official Title: Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study to Assess the Efficacy and Safety of Treatment With GSK3228836 in Participants With Chronic Hepatitis B Virus (B-Clear)
Actual Study Start Date : July 27, 2020
Estimated Primary Completion Date : October 20, 2022
Estimated Study Completion Date : October 20, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1: GSK3228836 300 mg + LD
Eligible participants on stable nucleos(t)ide treatment will receive 300 milligrams (mg) GSK3228836 once weekly for 24 weeks along with loading dose (LD) of 300 mg GSK3228836 on Day 4 and Day 11.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapy
Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: GSK3228836 300 mg + LD/ GSK3228836 150 mg + Placebo
Eligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapy
Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: GSK3228836 300 mg + LD/ Placebo
Eligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapy
Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 1: Placebo/ GSK3228836 300 mg + Placebo LD
Eligible participants on stable nucleos(t)ide treatment will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Drug: Nucleos(t)ide therapy
Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Experimental: Cohort 2: GSK3228836 300 mg + LD
Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 24 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Experimental: Cohort 2: GSK3228836 300 mg + LD/ GSK3228836 150 mg + Placebo
Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Experimental: Cohort 2: GSK3228836 300 mg + LD/ Placebo
Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.

Experimental: Cohort 2: Placebo/ GSK3228836 300 mg + Placebo LD
Eligible participants not currently on nucleos(t)ide therapy will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11.
Drug: GSK3228836
GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.

Drug: Placebo
Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.




Primary Outcome Measures :
  1. Percentage of participants achieving SVR [ Time Frame: Up to Week 48 ]
    Sustained response is defined as a continuous 24 weeks from end of GSK3228836 treatment during which levels of HBsAg in serum remain <LLOQ and HBV DNA< LLOQ.


Secondary Outcome Measures :
  1. Percentage of participants achieving HBsAg <LLOQ [ Time Frame: Up to Week 24 ]
    Participants achieving HBsAg <LLOQ at the end of treatment will be assessed.

  2. Percentage of participants achieving HBV DNA <LLOQ [ Time Frame: Up to Week 24 ]
    Participants achieving HBV DNA <LLOQ at the end of treatment will be assessed.

  3. Percentage of participants with alanine aminotransferase (ALT) normalization over time in absence of rescue medication [ Time Frame: Up to Week 48 ]
    Participants with Baseline ALT greater than (>) upper limit of normal (ULN) will be assessed for ALT normalization in absence of rescue medication over time.

  4. HBsAg level at indicated time points [ Time Frame: Day 1 to Week 48 ]
    Blood samples will be collected from participants to assess HBsAg level at indicated time points.

  5. Change from Baseline in HBsAg over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]
    Blood samples will be collected from participants to assess HBsAg level at indicated time points.

  6. HBV DNA level at indicated time points [ Time Frame: Day 1 to Week 48 ]
    Blood samples will be collected from participants to assess HBV DNA level at indicated time points.

  7. Change from Baseline in HBV DNA over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]
    Blood samples will be collected from participants to assess HBV DNA level at indicated time points.

  8. Hepatitis B virus e-antigen (HBeAg) level at indicated time points [ Time Frame: Day 1 to Week 48 ]
    Blood samples will be collected to assess HBeAg level of each participant.

  9. Change from Baseline in HBeAg level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]
    Blood samples will be collected to assess HBeAg level of each participant.

  10. Hepatatis B surface antibody (HBsAb) level at indicated time points [ Time Frame: Day 1 to Week 48 ]
    Blood samples will be collected to assess HBsAb level of each participant.

  11. Change from Baseline in HBsAb level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]
    Blood samples will be collected to assess HBsAb level of each participant.

  12. HBeAb level at indicated time points [ Time Frame: Day 1 to Week 48 ]
    Blood samples will be collected to assess HBeAb level of each participant.

  13. Change from Baseline in HBeAb level over time [ Time Frame: Baseline (Day 1) and up to Week 48 ]
    Blood samples will be collected to assess HBeAb level of each participant.

  14. Time to ALT normalization in absence of rescue medication [ Time Frame: Day 1 to Week 48 ]
    Time to ALT normalization in absence of rescue medication will be measured in participants with Baseline ALT>ULN.

  15. Percentage of participants achieving SVR over time [ Time Frame: Up to Week 24 ]
    Sustained response is defined as a continuous 24 weeks from end of GSK3228836 treatment during which levels of HBsAg in serum remain less than LLOQ and HBV DNA less than LLOQ.

  16. Area under the concentration-time curve (AUC) following administration of GSK3228836- Intensive pharmacokinetics (PK) [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  17. AUC following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  18. Concentration at the end of the dosing interval (Ctau) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  19. Ctau following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  20. Maximum observed concentration (Cmax) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  21. Cmax following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  22. Time of maximum observed concentration (tmax) following administration of GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  23. Tmax following administration of nucleos(t)ide therapy- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  24. Apparent subcutaneous plasma clearance for GSK3228836- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  25. Apparent oral plasma clearance for nucleos(t)ide- Intensive PK [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  26. Terminal half-life (T1/2) following administration of GSK3228836- All participants [ Time Frame: From Week 15 to Week 44 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  27. T1/2 following administration of nucleos(t)ide therapy- All participants [ Time Frame: Any one week between Week 14 to Week 24 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide therapy at indicated time points.

  28. Ctau following administration of GSK3228836- All participants [ Time Frame: From Week 1 to Week 25 ]
    Blood samples will be collected for PK analysis of GSK3228836 at indicated time points.

  29. Ctau following administration of nucleos(t)ide therapy- All participants [ Time Frame: From Week 1 to Week 25 ]
    Blood samples will be collected for PK analysis of nucleos(t)ide at indicated time points



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • At least 18 years of age at the time of signing the informed consent.
  • Participants who have documented chronic HBV infection greater than equal to (>=6) months prior to screening and not currently on nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naive) or must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit; OR Currently receiving stable nucleos(t)ide analogue therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
  • Plasma or serum HBsAg concentration >100 international units per milliliter (IU/mL).
  • Plasma or serum HBV DNA concentration: Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 IU/mL; Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.
  • ALT for treatment naive participants and for participants who are not currently receiving treatment: ALT <3 times ULN will be included initially if agreed by the independent data monitoring committee (IDMC) after review of safety data, the ALT inclusion criteria may be expanded to include participants with ALT <5 times ULN; ALT less than equal to (<=2) times ULN for participants who are receiving stable nucleos(t)ide analogue therapy.
  • Male and/or Female: A male participant is eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study treatment: Refrain from donating sperm AND be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or Must agree to use contraception/barrier as detailed below: Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential who is not currently pregnant. A female participant is eligible to participate: If she is not pregnant or breastfeeding AND at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1 percent per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment; A WOCBP must have both a confirmed menstrual period prior to the first dose of study intervention (additional evaluation [e.g., amenorrhea in athletes, birth control] should also be considered) and a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study treatment.
  • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • Capable of giving signed informed consent.

Exclusion Criteria:

  • Clinically significant abnormalities, aside from chronic HBV infection in medical history (e.g., moderate-severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant/unstable cardiac disease, uncontrolled diabetes, bleeding diathesis or coagulopathy) or physical examination.
  • Co-infection with Current or past history of Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Hepatitis D virus (HDV).
  • History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7. If only one parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted. Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: Liver biopsy (i.e., Metavir Score F4); Liver stiffness >12 kilopascals (kPa).
  • Diagnosed or suspected hepatocellular carcinoma as evidenced by the following: Alpha-fetoprotein concentration >=200 nanogram per milliliter (ng/mL); If the screening alpha fetoprotein concentration is >=50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.
  • History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer). Participants under evaluation for possible malignancy are not eligible.
  • History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).
  • History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).
  • Anti-neutrophil cytoplasmic antibodies (ANCA) at screening by itself won't be an exclusion criterion, but if results are borderline positive or positive: myeloperoxidase-ANCA (MPO-ANCA) (Perinuclear antineutrophil cytoplasmic antibodies [pANCA]) and proteinase 3- ANCA (PR3-ANCA) (Cytoplasmic antineutrophil cytoplasmic antibodies [cANCA]) analysis will be conducted; A discussion with the Medical Monitor will be required to review participant's complete medical history to ensure no past history or current manifestations of a vasculitic/inflammatory/auto-immune condition before inclusion in study is permitted.
  • Low complement C3 (C3) at screening by itself won't be an exclusion criterion, but if it is present: A discussion with the Medical Monitor is required to review participant's complete medical history to ensure no past history or current manifestations of vasculitic/inflammatory/auto-immune conditions.
  • History of alcohol or drug abuse/dependence: Current alcohol use as judged by investigator to potentially interfere with participant compliance; History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance. Refers to illicit drugs and substances with abuse potential. Medications that are used by the participant as directed, whether over-the-counter or through prescription, are acceptable and would not meet the exclusion criteria.
  • Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (<=2 weeks) or topical/inhaled steroid use.
  • Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids, will be excluded.
  • Currently taking, or took within 12 months of screening, any interferon-containing therapy.
  • Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel).
  • The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
  • Prior treatment with any oligonucleotide or small interfering ribonucleic acid (RNA) (Small interfering RNA [siRNA]) within 12 months prior to the first dosing day.
  • Fridericia's QT correction formula (QTcF) >=450 milliseconds (msec) (if single electrocardiogram [ECG] at screening shows QTcF>=450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
  • Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL), Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula (for Japan, Japanese Society of Nephrology Chronic Kidney Disease Initiative [JSN-CKDI equation]), International normalized ratio (INR) >1.25. Platelet count <140 times 10^9 cells/L, Total bilirubin >1.25 times ULN. For participants with benign unconjugated hyperbilirubinemia with total bilirubin >1.25 times ULN, discussion for inclusion to the study is required with the Medical Monitor, Urine albumin to creatinine ratio (ACR) >=0.03 mg/mg (or >=30 mg/g). In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement. In cases where participants have low urine albumin and low urine creatinine levels resulting in a urine ACR calculation >=0.03 mg/mg (or >=30 mg/g), the investigator should confirm that the participant does not have a history of diabetes, hypertension or other risk factors that may affect renal function and discuss with the Medical Monitor, or designee.
  • History of/sensitivity to GSK3228836 or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04449029


Contacts
Layout table for location contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT04449029    
Other Study ID Numbers: 209668
First Posted: June 26, 2020    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Chronic Hepatitis B
GSK3228836
Hepatitis B virus surface antigen
Nucleos(t)ide therapy
Sustained virologic response
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections