Hepatitis B virus (HBV) infection, especially chronic, is a significant worldwide medical problem. This is an exploratory study of the therapeutic mechanism of GSK3228836 in participants with chronic hepatitis B (CHB) on stable nucleos(t)ide therapy (which is the first line therapy for CHB). This study is a Phase IIa, multi-center open label exploratory study of the therapeutic mechanism of GSK3228836 in participants with hepatitis B virus e-antigen (HBeAg)-negative CHB on stable nucleos(t)ide therapy using repeat fine needle aspirations of the liver for intrahepatic immunophenotyping. It will investigate the virologic and immunologic correlates of hepatitis B virus surface antigen (HBsAg) loss observed in participants when treated for 12 weeks with 300 milligrams (mg) GSK3228836. Repeat fine needle aspirates of the liver will be performed to enable analysis of liver-resident immune cells to investigate any immunomodulatory properties of GSK3228836 and to study the biology of underlying treatment-associated liver flares. The study will consist of a screening, treatment, and post-treatment follow-up phase. Approximately 20 participants will be enrolled in the study.

Inclusion Criteria:

• Participants should be at least 18 years of age at the time of signing the informed consent.

• Participants who have documented chronic HBV infection >=6 months prior to screening and currently receiving stable nucleos(t)ide analogue therapy, 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 IU/mL

• Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.

• HBeAg-negative

• ALT less than or equal to (<=)2 times ULN

• No gender restriction.

• 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 i. Refrain from donating sperm ii. 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

  1) 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 (WOCBP) who is not currently pregnant.

• A female participant is eligible to participate:

  i. If she is not pregnant or breastfeeding. ii. and at least one of the following conditions applies:

  1. Is not a WOCBP
  2. 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 iii. A WOCBP must have both
  1. 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)
  2. and a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study treatment

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

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:

  1. Current or past history of Hepatitis C virus (HCV)
  2. Human immunodeficiency virus (HIV)
  3. Hepatitis D virus (HDV).

• History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by

  1. Both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7

     1) 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.

  2. Regardless of APRI or Fibrosure/FibroTest score participants will be excluded from the study if their past history includes one of the following criteria:

     1. Liver biopsy showing Metavir 4 or equivalent
     2. Liver stiffness >12 kilopascals (kPa)

• Diagnosed or suspected hepatocellular carcinoma as evidenced by the following

  1. Alpha-fetoprotein concentration >=200 nanograms (ng)/mL
  2. 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 enrolment.

• 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 antibody (ANCA) at screening by itself won't be an exclusion criterion - but if results are borderline positive or positive:

  1. Myeloperoxidase (MPO)-ANCA (perinuclear [p] ANCA) and Proteinase 3 (PR3)-ANCA (Cytoplasmic [c] ANCA) analysis will be conducted
  2. 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 compliment (C)3 at screening or Baseline by itself won't be an exclusion criterion-but if it is present

  a. 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

  1. Current alcohol use as judged by investigator to potentially interfere with participant compliance.

  2. History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance.

     1. 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 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

  1. Serum albumin <3.5 grams per deciliter (g/dL)

  2. Glomerular filtration rate (GFR) <60 mL/minute/1.73 per meter square as calculated by the Chronic kidney disease- Epidemiologic Collaboration (CKD-EPI) formula.

  3. International normalized Ratio (INR) >1.25

  4. Platelet count <140 times 10^9/liter (L)

  5. Total bilirubin >1.25 times ULN

     1. 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

  6. 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 1) 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.

IPD for this study will be made available via the Clinical Study Data Request site.

IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Up to Study Week 36

All-cause mortality, Serious adverse events and non-serious adverse events were reported for the Safety Population which consisted of all participants who received at least one dose of study treatment.