A Study of JNJ-73763989, Pegylated Interferon Alpha-2a and Nucleos(t)Ide Analogs in Participants With Chronic Hepatitis B Virus Infection

The purpose of this study is to evaluate the efficacy in terms of hepatitis B surface antigen (HBsAg) changes from baseline for the treatment regimens of 24 weeks of JNJ-73763989 + 24 weeks of nucleos(t)ide analog (NA) + 12 or 24 weeks of pegylated interferon alpha-2a (PegIFN-alpha-2a) (with immediate or delayed start of PegIFN-alpha-2a treatment).

JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism. Combination treatment with JNJ-73763989 and NA has the potential to specifically decrease HBV viral antigen levels and inhibit viral replication. Since HBsAg is immune suppressive, the direct reduction of HBsAg levels by JNJ-73763989 is anticipated to contribute to the restoration of the immune response that is impaired in chronic HBV infection. Pegylated interferon (PegIFN) is an approved drug for the treatment of chronic HBV infection and after a finite treatment duration of 48 weeks results in slightly increased HBsAg seroclearance rates. The primary hypothesis of this study is that at least one of the combination regimens of JNJ-73763989+NA+PegIFN-alpha-2a is more efficacious than NA treatment alone (standard of care), as measured by the primary efficacy endpoint. This study will be conducted in 3 periods: Screening Period (4 weeks), Treatment Period (24 weeks) and Follow-up (FU) Period (48 weeks), starting at Week 24. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, ophthalmologic examinations and physical examinations. Total duration of individual participation will be up to 76 weeks (including screening period).

Eligibility Criteria:
Inclusion Criteria:

* Medically stable based on physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening
* Participants must have a body mass index between 18.0 and 35.0 kilograms per meter square (kg/m\^2) inclusive
* Participants with chronic hepatitis B who should: a) be chronic hepatitis B e antigen (HBeAg) -negative; b) be anti-HBe antibody-positive; c) be currently receiving nucleos(t)ide analog (NA) treatment for at least 2 years prior to screening; d) have serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) less than (\<) 60 international unit/milliliter (IU/mL) on 2 sequential measurements at least 6 months apart; e) have alanine aminotransferase (ALT) values \< 2.0x upper limit of normal (ULN) on 2 sequential measurements at least 6 months apart
* Hepatitis B surface antigen (HBsAg) greater than (\>) 5 IU/mL at screening
* Fibroscan liver stiffness measurement less than or equal to (\<=) 9.0 kilopascal (kPa) within 6 months prior to screening

Exclusion Criteria:

* History or signs of cirrhosis or portal hypertension
* Evidence of hepatitis A, C, D, E virus infection, or human immunodeficiency virus (HIV) infection
* Liver disease of non-HBV etiology
* Clinically relevant alcohol or drug abuse within 12 months of screening
* Participants who meet any of the additional exclusion criteria for pegylated interferon alpha-2a (PegIFN- α2a) as described in local prescribing information (example, refer to Pegasys SmPC or Pegasys USPI) per the investigator's discretion. Key exclusion criteria for PegIFN- α2a include: a) Participants with signs or symptoms compatible with autoimmune disorders. b) Participants with bone marrow suppression. c) Participants with hypoglycaemia, hyperglycaemia, and/or diabetes mellitus, who cannot be effectively controlled by medication. d) Participants with pre-existing ophthalmologic disorders. e) Participants with one or more of the following laboratory abnormalities: i) Absolute neutrophil count less than (\<)1,500 cells/mm3 (\<1,000 cells/mm³ for black or African American participants). ii) Serum creatinine \>1.5x ULN. iii) Inadequately controlled thyroid function (thyroid stimulating hormone \[TSH\] and thyroxine \[T4\]). f) Participants with a history of a severe psychiatric disorder including severe depression, suicidal ideation and attempted suicide, or a current depression or other psychiatric disorder that is not adequately controlled on a stable medication regimen