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

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.


Eligibility 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.